JP2005508911A - Process for producing substituted pyrazoles - Google Patents

Abstract

The present invention is a process for producing a substituted pyrazole (I), a tautomer of a substituted pyrazole, or a salt of a substituted pyrazole or a tautomer, comprising R ^3A , R ^3B , R ^3C , Y ¹ , Y ² , It relates to a process wherein Y ³ , Y ⁴ and Y ⁵ are similar to those described in the specification. The method involves producing a mixture by a process comprising introducing hydrazone (II) and optionally substituted benzoyl halide (III) into the reactor, and heating the mixture to a temperature greater than 50 ° C.

Description

Cross-reference to related patent applications This patent is incorporated by reference in US provisional application 60 / 383,691 (filed May 28, 2002); 60 / 381,261 (filed May 17, 2002); and 60 / 324,987. Claim priority based on No. issue (filed on Sep. 25, 2001). The contents of these applications are incorporated herein by reference.

The present invention is directed to a process for producing substituted pyrazoles, including tautomers of substituted pyrazoles, and salts of substituted pyrazoles and tautomers. The present invention is also directed to compositions comprising compounds that can be used as intermediates in such methods (including methods for making such compositions). The present invention is further directed to pharmaceutical compositions, including substituted pyrazoles, tautomers and pharmaceutically acceptable salts prepared by such methods, including methods for making such compositions. The present invention is further directed to the use of compounds, tautomers and pharmaceutically acceptable salts prepared by such methods for treating various conditions.

BACKGROUND OF THE INVENTION Mitogen-activated protein kinases (MAPs) are a family of proline-specific serine / threonine kinases that activate their substrates by dual phosphorylation. Kinases are activated by various signals, such as nutrient and osmotic stress, UV light, growth factors, endotoxins and inflammatory cytokines. The p38 MAP kinase group is a MAP family of various isoforms, such as p38α, kP38β and p38γ. These kinases are involved in phosphorylation or activation of transcription factors (eg ATF2, CHOP and MEF2C), as well as other kinases (eg MAPKAP-2 and MAPKAP-3). The p38 isoform is activated by bacterial lipopolysaccharides, physical and chemical stresses and pro-inflammatory cytokines such as tumor necrosis factor (“TNF”) and interleukin-1 (“IL-1”). The product of p38 phosphorylation mediates the production of inflammatory cytokines such as TNF, IL-1 and cyclooxygenase-2.

  p38α kinase is, for example, inflammatory effects, generally arthritis; neuroinflammation; pain; fever; lung injury; cardiovascular disease; cardiomyopathy; stroke; ischemia; reperfusion injury; Injury and brain trauma; neurodegenerative disorders; central neuropathy disorders; liver disease and nephritis; gastrointestinal symptoms; ulcerative diseases; ophthalmic diseases; ophthalmological symptoms; glaucoma; acute damage to eye tissues and eye trauma; Diabetic nephropathy; skin-related symptoms; viral and bacterial infection; muscle pain due to infection; influenza; endotoxic shock; toxic shock syndrome; autoimmune disease; bone resorption disease; multiple sclerosis; Pathological (but non-malignant) symptoms such as hemangioma, vascular fibrosis of the nasopharynx and bone ischemic necrosis; benign and malignant tumors / neoplasms such as cancer; leukemia; lymphoma; systemic lupus erythematosus SLE); angiogenesis, for example tumor formation; and may be involved in or they cause metastases considered.

  TNF is a cytokine produced mainly by activated monocytes and macrophages. Excessive or unregulated TNF production (particularly TNF-α) has been implicated in mediating a number of diseases. For example, TNF is an inflammation (eg rheumatoid arthritis and inflammatory bowel disease), asthma, autoimmune disease, graft rejection, multiple sclerosis, fibrotic disease, cancer, fever, psoriasis, cardiovascular disease (eg post-ischemic) Reperfusion injury and congestive heart failure), lung disease (eg hyperoxic alveolar injury), bleeding, coagulation, radiation damage, and acute phase responses such as infection and sepsis and shock (eg septic shock and hemodynamics) It is thought that it can cause or be involved in what is observed during (shock). Chronic release of active TNF can result in cachexia and anorexia. And TNF can be fatal.

  TNF has also been implicated in infectious diseases. Examples of these include malaria, mycobacterial infection, meningitis. Examples of these include viral infections such as HIV, influenza viruses and herpes viruses such as type 1 herpes simplex virus (HSV-1), type 2 herpes simplex virus (HSV-2), cytomegalovirus (CMV), chickenpox Shingles virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and nasal trachea A flame etc. are also mentioned.

  IL-8 is another pro-inflammatory cytokine produced by monocytes, fibroblasts, endothelial cells and keratinocytes. This cytokine is associated with symptoms including inflammation.

  IL-1 is produced by activated monocytes and macrophages and is involved in the inflammatory response. IL-1 plays a role in numerous pathophysiological responses such as rheumatoid arthritis, fever and bone resorption reduction.

  TNF, IL-1 and IL-8 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of symptoms. Inhibition of these cytokines by inhibition of p38 kinase is beneficial in controlling, reducing and alleviating many of these disease states.

  Various pyrazoles have been described previously:

  In U.S. Pat. No. 4,000,281, Beiler describes 4,5-aryl / heteroaryl substituted pyrazoles with antiviral activity against both RNA and DNA viruses, eg against various viruses of the myxovirus, adenovirus, rhinovirus, and herpes group. Binon reports.

  WIPO International Publication WO 92/19615 (published 12 November 1992) describes pyrazole as a novel fungicide.

  In US Pat. No. 3,984,431, Cueremy and Renault reported a derivative of pyrazole-5-acetic acid as having anti-inflammatory activity, with [1-isobutyl-3,4-diphenyl-1H-pyrazol-5-yl] acetic acid being particularly Has been described.

  In US Pat. No. 3,245,093, Hinsgen et al. Report a method for producing pyrazole.

  WIPO International Publication WO 83/00330 (published February 3, 1983) describes a process for preparing diphenyl-3,4-methyl-5-pyrazole derivatives.

  WIPO International Publication WO 95/06036 (published March 2, 1995) reports a method for producing pyrazole derivatives.

  In US Pat. No. 5,589,439, T. Goto et al. Report tetrazole derivatives and their use as herbicides.

  EP 515,041 reports pyrimidinyl-substituted pyrazole derivatives as novel agricultural fungicides.

  Japanese Patent No. 4,145,081 reports pyrazole carboxylic acid derivatives as herbicides.

  Japanese Patent No. 5,345,772 reports a new pyrazole derivative as an inhibitor of acetylcholinesterase.

  Pyrazole has been reported to be useful for treating inflammation.

  Japanese Patent No. 5,017,470 reports the synthesis of pyrazole derivatives as anti-inflammatory, anti-rheumatic, anti-bacterial and anti-viral agents.

  European Patent No. 115640 (published on December 30, 1983) reported 4-imidazolyl-pyrazole derivatives as inhibitors of thromboxane synthesis and disclosed 3- (4-isopropyl-1-methylcyclohex-1-yl). -4- (imidazol-1-yl) -1H-pyrazole is specifically described.

  WIPO International Publication WO 97/01551 (published January 16, 1997) reports substituted pyrazoles as adenosine antagonists, 4- (3-oxo-2,3-dihydropyridazin-6-yl) -3-phenyl Pyrazole is specifically described.

  In US Pat. No. 5,134,142, Matsuo et al. Report that 1,5-diarylpyrazole has anti-inflammatory activity.

  In US Pat. No. 5,559,137, Adams et al. Reported pyrazole (1,3,4-substituted) as an inhibitor of cytokines used in the treatment of cytokine diseases, and 3- (4-fluorophenyl) -1- (4- Methylsulfinylphenyl) -4- (4-pyridyl) 5H-pyrazole is specifically described.

  WIPO International Publication WO 96/03385 (published February 8, 1996) reports 3,4-substituted pyrazoles as having anti-inflammatory activity, and 3-methylsulfonylphenyl-4-aryl-pyrazole and 3-aminosulfonyl Phenyl-4-aryl-pyrazole is specifically described.

  As inhibitors of p38 kinase, certain furans, pyrroles and pyrazolones, especially 3-pyridyl-2,5-diaryl-pyrrole, have been incorporated by Laszlo et al., Bioorg. Med. Chem. Letters, 8 (1998) 2689-2694 Describe.

  WIPO International Publication WO 98/52940 (PCT Patent Application US98 / 10436 (published November 26, 1998)) reports pyrazoles, compositions containing pyrazoles, and methods for treating p38-mediated disorders using these pyrazoles. To do.

  WIPO International Publication WO 00/31063 (PCT Patent Application US99 / 26007 (published June 2, 2000)) also reports pyrazoles, compositions containing those pyrazoles, and methods for making pyrazoles.

  In view of the importance of pyrazole in the prevention and treatment of several pathological conditions, particularly those associated with p38 kinase activity, TNF activity and / or cyclooxygenase-2 activity, there remains a need for a method for the production of substituted pyrazoles. Exists. The following disclosure describes such a method.

SUMMARY OF THE INVENTION The present invention is directed to a process for producing substituted pyrazoles that tend to inhibit p38 kinase activity, TNF activity and / or cyclooxygenase-2 activity.

に構造において対応する。
ここで、 In summary, therefore, the present invention is directed, in part, to a process for the preparation of substituted pyrazoles, tautomers of substituted pyrazoles, or salts of substituted pyrazoles or tautomers. The substituted pyrazole has the formula (I):

Corresponds to the structure.
here,

R ^3A , R ^3B and R ^3C are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy and alkoxyalkyl. Any carbon of alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy or alkoxyalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and cyano. The

One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═C (R ⁴ ) —. One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═N—. And ^{three of} Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are independently selected from the group consisting of = C (H)-and = N-.

R ⁴ is hydrogen, halogen, cyano, hydroxy, thiol, carboxy, nitro, alkyl, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxy , Carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylthio, carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy, carbocyclylheterocyclyl, heterocyclylalkyl, heterocyclyloxy, Heterocyclylalkoxy, amino, aminoalkyl, alkylamino, alkenylamino, alkini Amino, carbocyclylamino, heterocyclylamino, aminocarbonyl, alkoxy, alkoxyalkyl, alkenyloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, carbocyclyloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxycarboxy Kurylamino, alkoxycarbocyclylalkylamino, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylamino, alkylaminoalkylamino, carbocyclylalkylamino, alkylaminoalkylaminoalkylamino, alkylheterocyclyl Amino, heterocyclylalkylamino, alkylhe Terocyclylalkylamino, carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, alkylaminocarbonyl, alkylcarbonylamino, hydrazinyl, alkylhydrazinyl or carbocyclylhydrazinyl. Any substitutable member of such group is alkyl, alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, carbocyclyloxy Optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl and heterocyclylalkoxy.

に構造において対応する。任意置換ベンゾイルハロゲン化物は、式（ＩＩＩ）：

に構造において対応する。そしてＲ^Bは、ハロゲンである。 In one embodiment, the method includes producing the mixture by a method comprising introducing hydrazone and an optionally substituted benzoyl halide into the reactor. This mixture is heated to a temperature above 50 ° C. Here, the hydrazone has the formula (II):

Corresponds to the structure. The optionally substituted benzoyl halide has the formula (III):

Corresponds to the structure. R ^B is halogen.

に構造において対応する保護化ピラゾール中間体からなる。 In another embodiment, the method includes producing a composition. More than 30% (wt%) of this composition is of formula (IV):

Consists of a protected pyrazole intermediate corresponding in structure.

  In another embodiment, the method includes contacting the acid and toluene with a protected pyrazole intermediate corresponding in structure to formula (IV).

  In another embodiment, the method includes contacting a protected pyrazole intermediate corresponding in structure to formula (IV) with an acid to produce an acidic mixture. This acidic mixture is then contacted with a base. The temperature of the acidic mixture is kept below 65 ° C. during the time that the acidic mixture is formed and the time that the base is added to the acidic mixture.

  In another embodiment, the present invention includes contacting a protected pyrazole intermediate corresponding in structure to formula (IV) with an acid to produce an acidic mixture. The acidic mixture is then contacted with a base to produce a mixture having a higher pH. The mixture having a higher pH is then heated to a temperature above 25 ° C.

に構造において対応する。 In another embodiment, the invention includes contacting an unsubstituted piperidinyl intermediate with acetonitrile. Here, the unsubstituted piperidinyl intermediate has the formula (V):

Corresponds to the structure.

  In another embodiment, the method includes reacting a glycolate with an unsubstituted piperidinyl intermediate corresponding in structure to formula (V).

  The present invention is also directed in part to compositions (and methods for making such compositions) comprising compounds that can be used as intermediates in the above methods. More than 30% (wt%) of these compositions consist of compounds corresponding in structure to formula (IV).

  The present invention is also directed, in part, to compositions (or drugs) comprising compounds, tautomers and salts produced according to the present invention.

  The present invention is also directed, in part, to a method for producing a pharmaceutical composition comprising a compound, tautomer and salt produced according to the present invention.

  The invention is also directed, in part, to methods of treatment using compounds, tautomers and salts prepared according to the invention.

  Further advantages of Applicants' invention will become apparent to those skilled in the art upon reading this specification.

Detailed Description of the Preferred Embodiments This detailed description of the preferred embodiments is provided so that those skilled in the art will be able to adapt and apply the invention in its numerous forms if they can be optimally adapted to the requirements of a particular application. It is intended only to familiarize one skilled in the art with Applicants' invention, its principles, and its practical application. This detailed description and specific examples thereof, while indicating preferred embodiments of the invention, are intended for purposes of illustration only. Accordingly, the present invention is not limited to the preferred embodiments described in this specification and may be modified in various ways.
A. Compounds that can be prepared by the method of the invention

に構造において対応する化合物が挙げられる。ここで、 Compounds that can be prepared by the method of the present invention include the following formula (I):

Are compounds corresponding in structure. here,

R ^3A , R ^3B and R ^3C are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy and alkoxyalkyl. Any carbon of alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy or alkoxyalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and cyano. The

に構造において対応する。その他の実施態様において、化合物は、式（Ｉ−Ｂ）：

に構造において対応する。その他の実施態様において、化合物は、式（Ｉ−Ｃ）：

に構造において対応する。その他の実施態様において、化合物は、式（Ｉ−Ｄ）：

に構造において対応する。その他の実施態様において、化合物は、式（Ｉ−Ｅ）：

に構造において対応する。その他の実施態様において、化合物は、式（Ｉ−Ｆ）：

に構造において対応する。 In some preferred embodiments, R ^3C is hydrogen and R ^3A and R ^3B are independently from halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy and alkoxyalkyl. Selected from the group consisting of Any carbon of alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy or alkoxyalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and cyano. The In some such embodiments, the compound has the formula (IA):

Corresponds to the structure. In other embodiments, the compound has the formula (IB):

Corresponds to the structure. In other embodiments, the compound has the formula (IC):

Corresponds to the structure. In other embodiments, the compound has the formula (ID):

Corresponds to the structure. In other embodiments, the compound has the formula (IE):

Corresponds to the structure. In other embodiments, the compound has the formula (IF):

Corresponds to the structure.

に構造において対応する。いくつかの他の実施態様において、化合物は、式（Ｉ−Ｈ）：

に構造において対応する。いくつかの他の実施態様において、化合物は、式（Ｉ−Ｉ）：

に構造において対応する。 In some preferred embodiments, R ^3B and R ^3C are each hydrogen and R ^3A is halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, or alkoxyalkyl. . Any carbon of alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy or alkoxyalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and cyano. The In some such embodiments, the compound has the formula (IG):

Corresponds to the structure. In some other embodiments, the compound has the formula (IH):

Corresponds to the structure. In some other embodiments, the compound has Formula (I-I):

Corresponds to the structure.

In some preferred embodiments, R ^3A , R ^3B and R ^3C are independently from the group consisting of hydrogen, chloro, fluoro, hydroxy, cyano, amino, methyl, trifluoromethyl, ethyl, methoxy and trifluoromethoxy. Selected.

In some preferred embodiments, R ^3C is hydrogen and R ^3A and R ^3B independently consist of chloro, fluoro, hydroxy, cyano, amino, methyl, trifluoromethyl, ethyl, methoxy, and trifluoromethoxy. Selected from the group.

In some preferred embodiments, R ^3B and R ^3C are each hydrogen and R ^3A is chloro, fluoro, hydroxy, cyano, amino, methyl, trifluoromethyl, ethyl, methoxy, or trifluoromethoxy.

である。Ｙ¹、Ｙ²、Ｙ³、Ｙ⁴およびＹ⁵のうちの１つは＝Ｎ−、即ち、一原子と二重結合され、そして別の原子と単一結合される窒素原子：

である。そしてＹ¹、Ｙ²、Ｙ³、Ｙ⁴およびＹ⁵のうちの３つは独立して、＝Ｃ（Ｈ）−および＝Ｎ−からなる群から選択され、すなわちＹ¹、Ｙ²、Ｙ³、Ｙ⁴およびＹ⁵のうちの３つは独立して、以下の：

空なる群から選択される。 One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═C (R ⁴ ) —, ie, double bonded with one atom, single bonded with R ⁴ substituent, and further A carbon atom that is single-bonded with another atom:

It is. One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═N—, ie, a nitrogen atom that is double-bonded to one atom and single-bonded to another atom:

It is. And ^{three of} Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are independently selected from the group consisting of ═C (H) — and ═N—, ie, Y ¹ , Y ² , Y ^{3 of 3} , Y ⁴ and Y ⁵ are independently the following:

Selected from the empty group.

In some preferred embodiments, Y ¹ is ═C (H) — or ═N—; Y ² is ═C (R ⁴ ) —; Y ³ is ═N—; and Y ⁴ and Y ⁵ is each ═C (H) —.

In some preferred embodiments, Y ¹ and Y ³ are each ═N—; Y ² is ═C (R ⁴ ) —; and Y ⁴ and Y ⁵ are each ═C (H) —. is there.

Y ¹ and Y ³ are each ═N—; Y ² , Y ⁴ and Y ⁵ are each ═C (H) —.

Y ¹ , Y ² , Y ⁴ and Y ⁵ are each ═C (H) —; and Y ³ is ═N—.

R ⁴ is hydrogen, halogen, cyano, hydroxy, thiol, carboxy, nitro, alkyl, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxy , Carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylthio, carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy, carbocyclylheterocyclyl, heterocyclylalkyl, heterocyclyloxy, Heterocyclylalkoxy, amino, aminoalkyl, alkylamino, alkenylamino, alkini Amino, carbocyclylamino, heterocyclylamino, aminocarbonyl, alkoxy, alkoxyalkyl, alkenyloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, carbocyclyloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxycarboxy Kurylamino, alkoxycarbocyclylalkylamino, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylamino, alkylaminoalkylamino, carbocyclylalkylamino, alkylaminoalkylaminoalkylamino, alkylheterocyclyl Amino, heterocyclylalkylamino, alkylhe Terocyclylalkylamino, carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, alkylaminocarbonyl, alkylcarbonylamino, hydrazinyl, alkylhydrazinyl or carbocyclylhydrazinyl. Any substitutable member of such group is alkyl, alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, carbocyclyloxy Optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl and heterocyclylalkoxy.

In some preferred embodiments, R ⁴ is halogen, cyano, hydroxy, thiol, carboxy, nitro, alkyl, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, carbocyclyl, carbocyclylalkyl, carbocyclyl. Alkenyl, carbocyclyloxy, carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylthio, carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy, carbocyclylheterocyclyl, Heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, amino, aminoalkyl, alkylamino, Lucenylamino, alkynylamino, carbocyclylamino, heterocyclylamino, aminocarbonyl, alkoxy, alkoxyalkyl, alkenyloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, carbocyclyloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, Alkoxycarbocyclylamino, alkoxycarbocyclylalkylamino, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylamino, alkylaminoalkylamino, carbocyclylalkylamino, alkylaminoalkylaminoalkylamino , Alkylheterocyclylamino, heterocyclyl Alkylamino, alkylheterocyclylalkylamino, carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, alkylaminocarbonyl, alkylcarbonylamino, hydrazinyl, alkylhydrazinyl or carbocyclylhydrazinyl. Any substitutable member of such group is alkyl, alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, carbocyclyloxy Optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl and heterocyclylalkoxy.

In some preferred embodiments, R ⁴ is hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, carbocyclyloxy, carbocyclylalkoxy, carbocyclylthio, carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio, heterocyclyl. Sulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy, heterocyclyloxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, carbocyclylamino, heterocyclylamino, alkoxy, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonylamino, alkoxy Carbocyclylamino, alkoxycarbocyclylalkylamino, aminosulfinyl, Minosulfonyl, alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylamino, alkylaminoalkylamino, carbocyclylalkylamino, alkylaminoalkylaminoalkylamino, alkylheterocyclylamino, heterocyclylalkylamino, alkylheterocyclylalkylamino, carbosi It is cyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, alkylcarbonylamino, hydrazinyl, alkylhydrazinyl or carbocyclylhydrazinyl. Any substitutable member of such group is alkyl, alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, carbocyclyloxy Optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl and heterocyclylalkoxy.

In some preferred embodiments, R ⁴ is hydroxy, carbocyclyloxy, carbocyclylalkoxy, carbocyclylalkoxy, heterocyclyloxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, carbocyclylamino Heterocyclylamino, alkoxy, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonylamino, alkoxycarbocyclylamino, alkoxycarbocyclylalkylamino, alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylamino, alkylaminoalkylamino, Carbocyclylalkylamino, alkylaminoalkylaminoalkylamino, alkylheterocyclylamino, Russian heterocyclylalkyl amino, alkyl heterocyclylalkyl amino, carbocyclylalkyl heterocyclylamino, heterocyclyl heterocyclylalkyl amino, alkoxycarbonyl heterocyclylaminoalkyl, alkylcarbonylamino, hydrazinyl, alkylhydrazinyl, or carbocyclylalkyl hydrazinyl. Any substitutable member of such group is alkyl, alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, carbocyclyloxy Optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl and heterocyclylalkoxy.

In some preferred embodiments, R ⁴ is hydroxy, alkylthio, cyanocarbocyclyloxy, heterocyclyloxy, carbocyclylamino, dialkylaminoalkoxy, or dialkylaminoalkylamino.

In some preferred embodiments, R ⁴ is alkylthio.

In some preferred embodiments, R ⁴ is alkylsulfonyl.

In some preferred embodiments, R ⁴ is hydrogen.

に構造において対応するものが挙げられる。 Specific examples of preferred compounds include:

Are those corresponding in structure.

B. Compound Preparation Methods The compounds and salts of the present invention can be prepared from materials commonly available in the art.

ここで、Ｒ^Aは、例えばＣ₁〜Ｃ₆−アルキル、さらに好ましくはメチルまたはエチル、さらに好ましくはエチルであり得る。したがって例えばＢｃｏ保護化イソニペコチン酸エチルエステルは、市販のイソニペコチン酸エチルおよびジ−ｔ−ブチルジカルボネートから調製され得る：

メチルエステルは同様に、市販のイソニペコチン酸メチルおよびジ−ｔ−ブチルジカルボネートから調製され得る。 In a preferred embodiment, the synthesis begins by preparing an appropriately protected ester of isonipecotic acid. The protecting group can be, for example, a tert-butyloxycarbonyl group (or “Boc”). Boc-protected isonipecotate can be prepared from commercially available isonipecotate compounds and di-t-butyl dicarbonate:

Here, R ^A can be, for example, C ₁ -C ₆ -alkyl, more preferably methyl or ethyl, more preferably ethyl. Thus, for example, Bco-protected isonipecotic acid ethyl ester can be prepared from commercially available ethyl isonipecotate and di-t-butyl dicarbonate:

The methyl ester can likewise be prepared from commercially available methyl isonipecotate and di-t-butyl dicarbonate.

  Di-t-butyl dicarbonate is preferably charged to the reactor with about 1.01 to about 1.05 molar equivalents of isonipecotinate in a suitable solvent. The solvent can be, for example, tetrahydrofuran (“THF”). During the addition of isonipecotate, the temperature of the resulting mixture is preferably maintained at about 0 to about 15 ° C. After all of the isonipecotate has been added, the mixture is preferably warmed to room temperature (ie, about 20 to about 25 ° C.) and stirred for at least about 1 hour, more preferably about 1 to 3 hours, more preferably about 2 hours ( Eg stirred). Thereafter, the contents are preferably cooled to about 0 to about 10 ° C, more preferably to about 0 ° C, and the solvent is removed. If the solvent is THF, it can be removed, for example by vacuum distillation.

ここで、Ｙ¹、Ｙ²、Ｙ³、Ｙ⁴およびＹ⁵は上記と同様であるが、但し、Ｒ⁴が水素以外である場合には、Ｙ¹、Ｙ²、Ｙ³、Ｙ⁴およびＹ⁵のうちの1つは、本方法のこの段階では＝Ｃ（Ｒ⁴）−であり、いくつかの場合には、好ましくは＝Ｃ（ＳＣＨ₃）−であるのが望ましい。例証するために、ピラゾールの４−位置の置換基がその２−位置で置換されたピリミジニル基である置換ピラゾールを作製するのが望ましい場合には、メチルへテロアリール基は、多くの場合、好ましくは：

である。 The protected isonipecotate is then reacted with the appropriate methyl heteroaryl to produce a ketone:

Here, Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are the same as above, except that when R ⁴ is other than hydrogen, Y ¹ , Y ² , Y ³ , Y ⁴ and One of Y ⁵ is = C (R ⁴ )-at this stage of the method, and in some cases it is preferably = C (SCH ₃ )-. To illustrate, when it is desirable to make a substituted pyrazole in which the 4-position substituent of the pyrazole is a pyrimidinyl group substituted at the 2-position, the methylheteroaryl group is often preferred :

It is.

  Prior to initiating the reaction, the methyl anion of the methylheteroaryl is preferably first subjected to an organic solvent (e.g., Prepared by treating methylheteroaryl with about 2.35 to about 2.49 molar equivalents, more preferably about 2.42 molar equivalents of base in the presence of THF or ether, preferably THF. The base is, for example, lithium hexamethyldisyl azide (“LiHMDS”), lithium diisopropylamidoamide (“LDA”) or potassium tert-butoxide (“tBuOK”), with tBuOK being particularly preferred. Next, about 0.95 to about 1.03 molar equivalents, more preferably about 0.95 molar equivalents of Boc-protected isonipecotate (based on moles of methylheteroaryl) are added to the methyl anion mixture. The resulting mixture is preferably at least about 2 hours, more preferably about 2 to about 4 hours, more preferably about 3 to about 4 hours, about 0 to about 10 ° C, more preferably about 0 to about 5 ° C. Stir (stir) at a low temperature of about 5 ° C., more preferably. The temperature of the mixture is then preferably about 5 to about 15 ° C, more preferably about 10 ° C, in which case it is about 0.8 to about 1.2 hours, more preferably about Hold for 1 hour.

  Impurities can be removed from the resulting ketone product mixture using acid / base extraction. In a preferred embodiment, while maintaining the internal temperature below about 30 ° C., about 2.28 to about 2.52 molar equivalents, more preferably 2.4 molar equivalents of acid solution (based on moles of Boc-protected isonipecotate) is added to the reaction mixture. Added. The acid can be, for example, aqueous acetic acid. After addition of the acid solution, the aqueous phase is removed (eg, in a separatory funnel) and about 0.23 to about 0.27 molar equivalents, more preferably about 0.25 molar equivalents of acid solution (based on moles of Boc-protected isonipecotate) Is then added to the organic compound. The acid can be, for example, ammonium chloride or a dilute inorganic acid, such as 0.5 N hydrochloric acid. After the acid is added, the aqueous phase is preferably removed. The organic solvent can then be removed from the ketone product using, for example, distillation. For example, if the solvent is THF, it can be removed by gradually increasing the batch temperature under vacuum (eg, 200 torr) until it reaches about 60 to about 65 ° C.

The ketone is then reacted with toluenesulfonyl hydrazide to produce a hydrazone in a condensation reaction:

  In a preferred embodiment, the ketone product is combined with a solvent such as toluene, benzene or THF, but toluene is typically more preferred. Various impurities that may be present in the mixture (eg isonipecotic acid and / or ammonium chloride) preferably add water, stir the mixture for a short time (eg 30 minutes) and stir the mixture for a short time (eg It is removed by leaving for 1 hour) and then removing the aqueous layer. The remaining organic layer is then combined with toluenesulfonyl hydrazide. The molar ratio of toluenesulfonyl hydrazide to protected isonipecotate reagent (used in the ketone formation reaction) is preferably from about 0.87 to about 0.93, more preferably about 0.9.

  After the toluenesulfonyl hydrazide is combined with the ketone, the mixture is preferably heated to a temperature of about 66 to about 74 ° C., more preferably about 70 ° C. with stirring (eg, stirring). This heating and stirring is preferably continued for about 1.8 to about 2.2 hours, more preferably about 2 hours. The mixture is then preferably refluxed at about 70 ° C. under reduced pressure (eg, 200 torr) using a Dean-Stark vacuum trap, for example about 1.6 to about 2.4 hours, more preferably about 2 hours. The basic principles underlying the design of the Dean-Stark vacuum trap are well known in the art, such as Dean, EW & Stark, DD, “A Convenient Method for the Determination of Water in Petroleum and Other Organic Emulsions,” J. Indus And Eng. Chem., Vol. 12, No. 5. pp. 486-90 (May 1920), the contents of which are incorporated herein by reference.

  After heating, the mixture is preferably cooled to about -5 to about 5 ° C, more preferably about 0 ° C over a period of about 1.2 to about 1.8 hours, more preferably about 1.5 hours. Cooling is then preferably continued for at least about 10 hours, more preferably at least about 12 hours.

  After the cooling period, the solid is preferably separated (eg using filtration or centrifugation), washed with a solvent (eg toluene, benzene, THF and / or ethyl acetate, preferably ethyl acetate) and then dried. (Eg, raising the temperature to about 25 to about 40 ° C., more preferably about 40 ° C. under vacuum).

ここで、Ｒ^Bはハロゲン、好ましくはクロロである。 The hydrazone can then be reacted with an appropriately substituted benzoyl halide to produce a protected pyrazole intermediate:

Here, R ^B is halogen, preferably chloro.

  In a preferred embodiment, the hydrazone is placed in a clean dry reactor (preferably purged with nitrogen) from about 4.2: 1 to about 4.8: 1 (ml of solvent: g hydrazone solids), more preferably about 4.5: 1 (ml of solvent). Solvent of hydrazone solid g); about 1.05 to about 1.68 molar equivalents, more preferably about 1.4 molar equivalents of base (based on moles of hydrazone); and about 1.01 to about 1.25 molar equivalents, more preferably about 1.25 moles Charged with an equivalent amount of 4-chlorobenzoyl chloride (based on moles of hydrazone). The solvent can be, for example, THF or toluene. The base is, for example, LiHMDS, LDA, tBuOK or triethylamine, with taking ethylamine being particularly preferred. To enhance the reaction rate, an activator of 4-chlorobenzoyl chloride may be included in the reaction product as well. For example, about 0.1 molar equivalents of 4-N, N-dimethylaminopyridine (based on moles of hydrazone reagent) may be included. 4-Chlorobenzoyl chloride is preferably charged gradually into the reactor after hydrazone, solvent, base and optional activator are charged. Once 4-chlorobenzoyl chloride is charged, the reaction mixture is preferably at a temperature of at least about 50 ° C, more preferably greater than 50 ° C, more preferably greater than 50 ° C and less than about 65 ° C, more preferably Heat to about 65 ° C. Heating is then preferably continued for longer than 30 minutes, more preferably at least about 1 hour, more preferably from about 1 to about 2 hours, more preferably about 2 hours. The resulting product mixture is then preferably cooled to room temperature.

  It is particularly preferred to isolate the protected pyrazole product from the product mixture. For example, Applicants have found that such isolation generally improves product yield, purity and reproducibility later. Water can be added to the product mixture to remove existing salt impurities (and any other impurities that are soluble in water). The product mixture is then agitated (stirred), preferably for at least about 0.5 hours, more preferably from about 0.5 to about 1 hour, more preferably about 0.5 hour. Phase separation then occurs and the aqueous layer is removed. To remove impurities and color from the organic compound, an aqueous salt solution (generally at least about 25% (wt%), more preferably about 3.5 to about 3.88 molar equivalents (based on moles of hydrazone)), more preferably about 3.66 molar equivalents (based on moles of hydrazone)) are then (or alternatively) added to the organic phase. The salt in the salt solution preferably does not exceed the saturation concentration at room temperature. A particularly useful salt solution is aqueous ammonium chloride. As with water separation, the combined salt solution and organic compound are stirred for about 0.5 to about 1 hour, more preferably about 0.5 hour. Phase separation then occurs and the aqueous layer is removed. The separation can be performed at room temperature.

After phase separation to remove impurities, the protected pyrazole intermediate is preferably precipitated from an organic solvent. This is preferably accomplished at least in part using an antisolvent. An antisolvent is a secondary solvent that, when mixed with a primary solvent containing a solubilizing component (in this case, a protected pyrazole intermediate), makes the component less soluble than in the primary solvent alone. The antisolvent can in this case be, for example, a C ₁ -C ₆ alcohol, preferably isopropyl alcohol (“IPA”). In a preferred embodiment, a preheated mixture of IPA in water (preferably containing about 1: 1 (vol: vol) IPA: water), preferably above 25 ° C, more preferably from about 50 to about 60 ° C, (Preferably at a temperature of 55 ° C.) is added to the reaction mixture (preferably at a temperature above 25 ° C.) over a period of at least 1 hour, more preferably about 1 to about 2 hours, more preferably about 1 hour. And more preferably after preheating to a temperature of about 50 to about 60 ° C., more preferably 55 ° C.). After the addition is complete, the solution is preferably at a temperature above 25 ° C, more preferably about 50 to about 60 ° C, more preferably 55 ° C, for at least about 3 hours, more preferably about 3 to about 5 hours, more preferably Is stirred (eg, stirred) for about 3 hours. The solution is then cooled, preferably at a rate of about 0.1 to about 1 ° C / minute, more preferably at a rate of about 0.3 ° C / minute, to a temperature of about 20 to about 28 ° C, more preferably about 25 ° C. The The slurry is then held at a temperature of about 20 to about 28 ° C, more preferably about 25 ° C for at least about 2 hours, more preferably about 2 to about 24 hours, more preferably about 2 hours. The precipitate is then preferably removed, for example by filtration (eg using a 4 micron filter cloth) or centrifugation. The solid is preferably washed with additional antisolvent and / or water and dried. The solid can be dried, for example, using heat, optionally under vacuum. When heat is used, the temperature is preferably about 70 to about 80 ° C, more preferably about 80 ° C. The concentration of the protected pyrazole intermediate in the cake is preferably greater than 30% (wt%), in a particularly preferred embodiment at least about 50% (wt%), more preferably at least about 75% (wt%), More preferably it is at least about 95% (wt%), more preferably at least about 97% (wt%), more preferably at least about 98.5% (wt%).

Once isolated, the protected pyrazole intermediate is preferably deprotected to produce the deprotected pyrazole intermediate (also referred to in this patent as the “unsubstituted piperidinyl intermediate”):

  In a preferred embodiment, the reactor is first charged with the protected pyrazole intermediate and solvent to produce a slurry. The slurry is preferably agitated (eg, stirred). The solvent is, for example, water, THF, ethyl acetate, ethanol, butanol, isopropyl alcohol, acetone or toluene, and preferably THF or toluene. The amount of solvent is preferably at least about 1: 1 (solvent ml: protected pyrazole g), more preferably about 2.5: 1 (solvent ml: protected pyrazole g).

To deprotect the pyrazole intermediate, a base can be added to the slurry, typically in the presence of heat (preferably at a temperature above 25 ° C. and below 80 ° C.). However, in a more preferred embodiment, an acid is used. In this embodiment, about 2 to about 12 molar equivalents, more preferably about 8.0 molar equivalents of acid (based on moles of the protected pyrazole intermediate) are gradually added to the mixture to provide a protecting group for the pyrazole intermediate. Remove. A number of acids are suitable, but the acids preferably have a pKa of about -3 or less. In particularly preferred embodiments, the acid is HCl or H ₂ SO ₄ , with HCl generally being more preferred. When the acid includes HCl, the solvent is preferably toluene. For example, THF tends to react with HCl to produce chlorobutyl alcohol, which in turn tends to act as an alkylating agent that can produce additional impurities. In some preferred embodiments, the deprotection reaction mixture is maintained at a temperature of less than 65 ° C. In some such preferred embodiments, the reaction mixture is held at less than about 30 ° C., more preferably at room temperature, preferably for at least about 1 hour. In some other preferred embodiments, the reaction mixture is more preferably about 1.5 to about 3 hours at a temperature of about 25 to about 100 ° C, more preferably about 65 to about 75 ° C, more preferably about 70 ° C. Is maintained for about 2.0 to about 2.5 hours, more preferably about 2 hours. After such heating, the mixture is preferably cooled to about 20 to about 35 ° C, more preferably about 25 ° C.

このスキームから分かるように、メチルチオ基は、好ましくは先ず、適切な溶媒、例えばジクロロメタン、アセトニトリルおよび／またはテトラヒドロフラン中の酸化剤（例えばオキソン（登録商標）、Ｈ₂Ｏ₂または３−クロロ過安息香酸（「ｍＣＰＢＡ」））でメチルスルホニルに酸化される。酸化後、メチルスルホニル基は、好ましくは適切な溶媒、例えばテトラヒドロフラン、ジオキサン、ジメチルホルムアミドまたはアセトニトリル中の適切な試薬（典型的にはアミンまたは酸化物）で置換される。酸化物試薬は、典型的には、適切な溶媒、例えばテトラヒドロフラン、ジオキサンまたはジメチルホルムアミド中の適切な塩基（例えばＬｉＨＭＤＳ、ＮａＨ、ＬＤＡまたはｔＢｕＯＫ）を用いてそのそれぞれのアルコールから生成され得る。置換反応は、好ましくは約20〜約200℃の温度で実行される。これらの条件下で、ピラゾールの１−位置のトシル保護基が典型的には同時に脱保護される。ピペリジニル基の脱保護はその後、ジクロロメタンまたはジオキサンのような溶媒中のトリフルオロ酢酸またはＨＣｌを用いて成し遂げられ得る。しかしながら典型的なさらに好ましい実施態様では、ピペリジニル基の脱保護は、一般的に保護化ピラゾール中間体に関して上記された脱保護プロトコールを用いて成し遂げられる。 As noted above, when the desired compound is a non-hydrogen R ⁴ substituent, the carbon attached to the R ⁴ substituent is the methylthio group (“—SCH” in the methyl heteroaryl reagent (discussed above with the ketone preparation). ₃ ") is often preferred. In other words, ^one of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ , which is preferably ═C (R ⁴ ) —, is preferably ═C (SCH ₃ ) — (which is Particularly preferred when the desired R ⁴ substituent is an amine or an oxide). For example, when such a methylthio group is used, the above deprotection protocol is preferably also modified to replace the methylthio group with an appropriate reagent to attach the desired R ⁴ substituent. Thus, for example, when R ⁴ is present at two positions of the pyrimidinyl group, the protected pyrazole can be deprotected simultaneously while replacing the methylthio group with the desired R substituent using the following general scheme:

As can be seen from this scheme, the methylthio group is preferably first of all an oxidant (eg Oxone®, H ₂ O ₂ or 3-chloroperbenzoic acid in a suitable solvent such as dichloromethane, acetonitrile and / or tetrahydrofuran. ("MCPBA")) and oxidized to methylsulfonyl. After oxidation, the methylsulfonyl group is preferably replaced with a suitable reagent (typically an amine or oxide) in a suitable solvent such as tetrahydrofuran, dioxane, dimethylformamide or acetonitrile. Oxidizing reagents can typically be generated from their respective alcohols using a suitable base (eg LiHMDS, NaH, LDA or tBuOK) in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide. The substitution reaction is preferably carried out at a temperature of about 20 to about 200 ° C. Under these conditions, the tosyl protecting group at the 1-position of the pyrazole is typically deprotected simultaneously. Deprotection of the piperidinyl group can then be accomplished using trifluoroacetic acid or HCl in a solvent such as dichloromethane or dioxane. However, in a typical more preferred embodiment, deprotection of the piperidinyl group is accomplished using the deprotection protocols generally described above for protected pyrazole intermediates.

  After deprotection (including any substitution reaction), the majority of the pyrazole is present in the aqueous phase of the mixture. Additional water is preferably added and the resulting mixture is agitated (stirred) for about 10 to about 60 minutes, more preferably about 20 minutes. The organic compound is then preferably removed from the aqueous layer. In a preferred embodiment, about 7 to about 9 molar equivalents, more preferably about 8.2 molar equivalents of base (based on moles of protected pyrazole intermediate) until the pH is about 11 to about 13, more preferably about 12.6. Are gradually added. The base is, for example, sodium acetate, potassium acetate, potassium hydroxide and sodium hydroxide, with sodium hydroxide being preferred. After the base addition is complete, the mixture is preferably heated gradually to a temperature above 25 ° C, more preferably from about 65 to about 80 ° C, more preferably about 75 ° C. Heating is then preferably continued for at least about 1 hour, more preferably about 1 to about 3 hours, more preferably about 1.5 to about 2 hours, more preferably about 2 hours. The mixture is then preferably cooled to about 0 ° C. to room temperature (more preferably about 2 ° C.) over a period of about 2 to about 5 hours (more preferably about 3 hours) and then about 2 to about 6 hours. (More preferably about 4 hours), maintained at about 0 ° C to room temperature (more preferably about 2 ° C). The precipitate can be collected using, for example, filtration (eg, using a 4 micron filter cloth) or centrifugation. The resulting cake is preferably washed with deionized water (preferably multiple times) and with acetonitrile. The cake can be air dried until a constant weight is reached. If necessary, the cake may alternatively (or additionally) be dried under vacuum at a temperature from room temperature to about 70 ° C.

  The deprotected pyrazole cake is preferably ground with acetonitrile. This grinding tends to beneficially cause polymorph transformations that improve the physical properties of the deprotected pyrazole intermediate for downstream processes. In a preferred embodiment, acetonitrile has an acetonitrile to solid ratio of at least about 4: 1 (ml: g), more preferably from about 3: 1 to about 8: 1 (ml: g), more preferably about 5: 1. (Ml: g) is added to the deprotected pyrazole solid in such an amount. The future is then preferably heated to a temperature above 25 ° C, more preferably at least about 75 ° C, more preferably from about 80 to about 82 ° C, more preferably to the reflux temperature. This heating is preferably continued for at least about 1 hour, more preferably about 1 to about 6 hours, more preferably about 1 hour. The mixture is then preferably at least about 15 minutes, more preferably about 0.5 to about 2 hours, more preferably about 0.5 hours, less than about 30 ° C, more preferably about 2 to about 20 ° C, more preferably about 2 ° C. It is cooled to less than -20 ° C, more preferably to about 5 ° C. The solid can then preferably be collected using, for example, filtration (eg, using a 4 micron filter cloth) or centrifugation. Thereafter, the solid is preferably washed with acetonitrile and then optionally dried. Drying can be accomplished, for example, by air drying to a constant weight or by heating the solid to a temperature of at least at least about 50 ° C, more preferably from about 40 to about 85 ° C, more preferably about 85 ° C. This heating can optionally be performed under vacuum. The resulting deprotection concentration in the cake is preferably at least about 95% (% by weight), more preferably at least about 96% (% by weight), more preferably at least about 99% (% by weight).

The deprotected pyrazole intermediate pair is preferably reacted with glycolate to produce the desired N- (2-hydroxyacetyl) -5- (4-piperidyl) pyrazole:

  In a preferred embodiment, the solvate form of N- (2-hydroxyacetyl) -5- (4-piperidyl) pyrazole product is produced. This is because N- (2-hydroxyacetyl) -5- (4-piperidyl) pyrazole is N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4- Chlorophenyl) pyrazole is particularly preferred. As discussed below, 1-methyl-2-pyrrolidinone of N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole ("" N-methylpyrrolidinone "or" NMP ") solvates are often particularly preferred. In that case, the solvate into another crystalline form, in particular to the type 1 crystal N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole. Further conversion is often preferred.

The glycolic acid ester is preferably a C ₁ -C ₆ -alkyl glycolate (ie, R ^C in the above reaction is C ₁ -C ₆ -alkyl), more preferably ethyl glycolate or butyl glycolate, more preferably It is butyl glycolate. For example, its low cost and the fact that it has a boiling point above the preferred temperature for the reaction gives rise to a selection for butyl glycolate.

  The deprotected pyrazole is preferably from about 2.0 to about 8.0 molar equivalents, more preferably from about 2.0 to about 3.0 molar equivalents, more preferably from about 2.0 molar equivalents in the presence of a solvent or with a net glycolic acid ester (ie without solvent). The reactor is charged with 2.5 molar equivalents of glycolic acid ester. If a solvent is used, it preferably comprises a polar aprotic solvent and / or an alcohol. The solvent is preferably such that N- (2-hydroxyacetyl) -5- (4-piperidyl) pyrazole is substantially soluble at elevated temperatures (eg at least about 60 ° C. for alcohols, aprotic solvents In which the N- (2-hydroxyacetyl) -5- (4-piperidyl) pyrazole is N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4 -Pyrimidinyl) -3- (4-chlorophenyl) pyrazole). The solubility of N- (2-hydroxyacetyl) -5- (4-piperidyl) pyrazole at high temperature is preferably at least about 10 of N- (2-hydroxyacetyl) -5- (4-piperidyl) pyrazole in a solvent. It is sufficient to provide a% (wt%) solution, more typically at least about 15% (wt%) solution, more typically at least about 20% (wt%) solution. The solubility of N- (2-hydroxyacetyl) -5- (4-piperidyl) pyrazole at room temperature is preferably about 5 of N- (2-hydroxyacetyl) -5- (4-piperidyl) pyrazole in a solvent. % (Wt%) solutions, more typically from about 0.1 to about 5% (wt%) solutions, more typically from about 1 to about 3% (wt%) solutions. Examples of such solvents include dimethylformamide (“DMF”) and / or NMP (particularly N- (2-hydroxyacetyl) -5- (4-piperidyl) pyrazole is N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole). Suitable solvents may also include dimethyl sulfoxide (“DMSO”) hypothetically. The preferred amount of solvent will vary with the solvent. Typically from about 1: 1 to about 8: 1 (solvent mL: deprotected pyrazole g), more typically from about 2: 1 to about 4: 1 (mL: g), more typically about A 2: 1 (mL: g) solvent is preferably present. In general, the preferred solvent is NMP. The remaining discussion thus illustrates the invention using NMP as the solvent.

  The reaction can be carried out under standard peptide coupling conditions as described in Schemes D-1 and D-2 in PCT Publication WO 00/31063, and Example D-1 (Step 5). However, in a generally more preferred embodiment, the reaction is 1,8-diazabicyclo [5.4.0] undec-7-ene ("DBU") and / or 1,5-diazabicyclo [4.3.0] non. It is carried out in the presence of -5-ene, with 1,8-diazabicyclo [5.4.0] undec-7-ene being particularly preferred. It is hypothesized that N, N, N ′, N′-tetraethyl-N ″ -cyclohexylguanidine may alternatively be used. Preferably at least about 0.05 molar equivalents, more preferably about 0.1 to about 0.4 molar equivalents, Preferably about 0.1 molar equivalent of catalyst (preferably 1,8-diazabicyclo [5.4.0] undec-7-ene) is present (based on moles of deprotected pyrazole).

  After charging the components to the reactor, the resulting mixture is preferably at a temperature above 25 ° C, more preferably at least about 60 ° C, more preferably from about 90 to about 150 ° C, more preferably about 110 ° C. It is stirred while being heated to a temperature of ° C. Heating is preferably continued until no more than 5% (more preferably less than about 3%, more preferably less than about 0.5%) of the starting material remains in the reaction mixture. The amount of starting material can be detected in real time using, for example, liquid chromatography analysis. Usually, heating is continued for at least about 2 hours, more typically about 2 to about 4 hours, more typically about 2 to about 3 hours, and more typically about 3 hours.

  In many preferred embodiments, it is preferred to produce a solvate of N- (2-hydroxyacetyl) -5- (4-piperidyl) pyrazole. In such cases, the mixture is preferably at a temperature of about 80 ° C. or less, more preferably about about 30 minutes, more preferably at least about 1 to about 2 hours, more preferably about 1 hour. It is cooled to 20 ° C to about 60 ° C, more preferably about 25 ° C. After this initial cooling period, the mixture is preferably at a temperature below 20 ° C., more preferably about 0, over a period of at least about 15 minutes, more preferably about 30 to about 60 minutes, more preferably about 30 minutes. It is cooled to about 5 ° C, more preferably about 0 ° C. This cooling is preferably continued for at least about 1 hour, more preferably about 1 to about 2 hours, more preferably about 2 hours.

  In a particularly preferred embodiment, an antisolvent is added while the mixture is cooled. In a particularly preferred embodiment, the antisolvent is added during the primary cooling period, especially at the end of the primary cooling period. The antisolvent is preferably a polar solvent, such as water, ethyl acetate, methanol, isopropylpyr alcohol and / or ethanol, with ethanol being particularly preferred. Preferably about 0.2: 1 to about 10: 1 (antisolvent mL: deprotected pyrazole g), more preferably about 0.2: 1 to about 0.3: 1 (mL: g), more preferably about 0.22 (mL: g) ) Anti-solvent is added. When antisolvent is added, cooling is preferably continued for about 1 to about 6 hours, more preferably about 1 hour. The mixture is then cooled to a temperature of about -5 to about 30 ° C (more preferably about 0 to about 2 ° C), preferably over a period of about 15 minutes to about 5 hours (more preferably about 30 minutes), The temperature is maintained for about 1 to about 24 hours, more preferably about 2 hours.

  The resulting solid is preferably collected, for example by filtration (eg using a 4 micron filter cloth) or by centrifugation, washed at least once (preferably twice) with NMP and / or antisolvent and dried. Is done. The resulting cake preferably contains at least about 95% (wt%), more preferably at least about 98% (wt%), more preferably at least about 99 wt% solvate. The amount of NMP to N- (2-hydroxyacetyl) -5- (4-piperidyl) pyrazole in the solvate is typically a molar ratio of less than about 200 ppm (or 0.02 wt%) to about 1: 1. (Especially when the solvate is an NMP solvate).

  N- (2-hydroxyacetyl) -5- (4-piperidyl) pyrazole is N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole In a number of preferred embodiments, wherein the NMP solvate is isolated, then Form I crystalline N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4-pyrimidinyl) -3- ( Converted to 4-chlorophenyl) pyrazole.

  In a particularly preferred embodiment, the solvate is charged to the reactor with a polar solvent. Such solvents are, for example, water, ethyl acetate, methanol, isopropylpyr alcohol and / or ethanol, preferably ethanol (especially if ethanol is an antisolvent that is wiped into the solvate mixture during cooling). ). Preferably about 50: 1 to about 5: 1 (ml of solvent: NMP solvate solid g), more preferably about 10: 1 to about 8: 1 (ml of solvent: NMP solvate solid g), more preferably Approximately 9: 1 (solvent ml: NMP solvate solid g). In addition to the solvent, about 0.01 to about 0.4 equivalents, more preferably about 0.12 to about 0.09 equivalents of DBU (based on moles of N- (2-hydroxyacetyl) -5- (4-piperidyl) pyrazole) is optional Can be charged to the reactor. The presence of this small amount of DBU tends to be beneficial, for example, to saponify any bis-glycolate impurities present in the mixture.

  The solvate / solvent mixture is preferably heated to a temperature above 25 ° C, more preferably to at least about 50 ° C, more preferably from about 50 to about 80 ° C, more preferably to the reflux temperature. Heating is preferably continued for at least 1 hour, more preferably from about 1 hour to about 5 hours, more preferably about 4 hours. One hour typically converts the solvate to Form 1 crystalline N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole. Applicants have found that this is sufficient, but the applicants have found that additional heating can often be beneficial to obtain a purer product.

  After heating, the mixture is preferably at a temperature below about 30 ° C., more preferably from about 0 ° C. to over a period of at least about 1 hour, more preferably from about 1.5 to about 5 hours, more preferably about 3 hours. Cool to about 30 ° C, more preferably about 15 ° C. The solid is then collected, for example, by filtration (eg, using a 4 micron filter cloth) or centrifugation. The cake is then preferably washed (preferably at least twice) with a polar solvent (preferably the solvent used during reflux) (preferably in a displacement wash) and then dried. The cake preferably contains less than about 500 ppm NMP, more preferably less than 300 ppm NMP, more preferably less than 250 ppm NMP.

C. Compounds of the Invention in Tautomeric Form The present invention is also directed to compounds of formula (I) in tautomeric form. As illustrated below, the pyrazoles of formulas (A) and (B) are magnetically and structurally equivalent due to the prototrophic tautomerism of hydrogen:

D. Compounds of the Invention Having One or More Asymmetric Carbons The present invention also includes compounds of formula (I) that contain one or more asymmetric carbons. It is known to those skilled in the art that the pyrazoles of the present invention having asymmetric carbon atoms can exist in diastereomers, racemates or optionally in active form. All of these forms are contemplated within the scope of the present invention. In particular, the present invention includes enantiomers, diastereomers, racemic mixtures, and other mixtures thereof.

E. Salts of the Compounds of the Invention The compounds of the invention can be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound (and / or its crystal structure), the salt of the compound may be pharmacologically stable at one or more physical properties of the salt, such as various temperatures and humidity, or desirable solubility in water or oil. May be beneficial for sex enhancement. In some cases, a salt of a compound can be used as an aid in the isolation, purification and / or degradation of the compound.

  If the salt is intended to be administered to a patient (eg, as used in an in vitro situation), the salt is preferably pharmaceutically acceptable. Pharmaceutically acceptable salts include those commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts typically may be prepared by conventional means, for example using a compound of the invention, by reacting the appropriate acid or base with the compound.

  Pharmaceutically acceptable acid addition salts of the compounds of this invention can be prepared from inorganic or organic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic acid and sulfonic acid class organic acids. Specific examples of suitable organic acids include acetic acid, trifluoroacetic acid, formic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, digluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, malein Acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylate, stearic acid, salicylic acid, p-hydrobenzoic acid, phenylacetic acid, mandelic acid, embonate (pamoate), methanesulfonic acid, ethanesulfonic acid , Benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, algenic acid, b-hydroxybutyric acid, galactaric acid, galacturonic acid, adipic acid, alginic acid, bisulfuric acid , Butyric acid, show Uric acid, camphorsulfonic acid, cyclopentanepropionic acid, dodecylsulfuric acid, glycoheptanoic acid, glycerophosphoric acid, hemisulfuric acid, heptanoic acid, hexanoic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, palmoate, pectic acid, persulfate , 3-phenylpropionic acid, picric acid, pyruvic acid, thiocyanic acid, tosylate and undecanoic acid.

Examples of the pharmaceutically acceptable base addition salt of the compound of the present invention include metal salts and organic salts. Preferred metal salts include alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts, and other physiologically acceptable metal salts. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts are from tertiary and quaternary amine salts such as tromethamine, diethylamine, N, N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Can be made. Basic nitrogen-containing groups include lower alkyl (C ₁ -C ₆ ) halides (eg methyl, ethyl, propyl and butyl chloride, bromide and iodide), dialkyl sulfates (eg dimethyl, diethyl, dibutyl and diamyl sulfate). ), Long chain halides (eg decyl, lauryl, myristyl and stearyl chloride, bromide and iodide), arylalkyl halides (eg benzyl and phenethyl bromide) and the like.

Particularly preferred salts of the compounds of the present invention include hydrochloric acid (HCl) salt, trifluoroacetic acid (CF ₃ COOH or “TFA”) salt, mesylate salt and tosylate salt.
F. Prevention or treatment of symptoms using compounds prepared according to the present invention

  The present invention relates in part to symptoms (typically pathological) in mammals (eg, humans, pets, farm animals, laboratory animals, zoo animals or wild animals) that have or have been treated to have such symptoms. Directed to methods for preventing or treating symptoms).

  Some embodiments of the invention are directed to methods for preventing or treating p38-mediated symptoms. As used herein, the term “p38-mediated condition” refers to the control of p38 kinase itself, or by p38 kinase that releases another factor, eg, IL-1, IL-6 or IL-8. It refers to any symptom (especially pathological symptoms, ie diseases and disorders) in which p38 kinase (especially p38α kinase) plays a role. For example, a disease state in which IL-1 is a major component whose production or action is exacerbated or secreted in response to p38 is therefore considered a disorder mediated by p38.

  The compounds of the invention generally tend to be useful for treating or preventing pathological conditions, examples of which include, but are not limited to:

  (a) inflammation;

  (b) arthritis such as rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus arthritis, juvenile arthritis, osteoarthritis and gouty arthritis;

  (c) neuroinflammation;

  (d) pain (ie use of the compound as an analgesic), eg neuropathic pain;

  (e) fever (ie use of the compound as an antipyretic);

  (f) Lung disorder or inflammation, such as adult respiratory distress syndrome, pulmonary sarcoidosis, asthma, silicosis and chronic pulmonary inflammatory disease;

  (g) cardiovascular diseases such as atherosclerosis, myocardial infarction (eg post-myocardial infarction indication), thrombosis, congestive heart failure, cardiac reperfusion injury, and complications associated with hypertension and / or heart failure such as blood vessels Sexual organ damage;

  (h) cardiomyopathy;

  (i) stroke, such as ischemic and hemorrhagic stroke;

  (J) ischemia, eg, ischemia due to cerebral ischemia and cardiac / coronary artery bypass;

  (K) reperfusion injury;

  (L) kidney reperfusion injury;

  (M) cerebral edema;

  (N) nerve trauma and brain trauma, such as non-opening head injury;

  (o) neurodegenerative disorders;

  (p) central nervous system disorders (examples of which include disorders with inflammatory or apoptotic components), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury and peripheral Sex neuropathy;

  (Q) liver disease and nephritis;

  (R) gastrointestinal symptoms such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis;

  (s) Ulcerative diseases such as gastric ulcers;

  (t) Eye diseases such as retinitis, retinopathy (eg diabetic retinopathy), uveitis, ocular photophobia, non-glaucoma optic atrophy and age-related macular degeneration (ARMD) (eg ARMD atrophic form) ;

  (u) Ophthalmological symptoms such as corneal transplant rejection, ocular neovascularization, retinal neovascularization (eg, neovascularization following injury or infection) and post-lens fiber proliferation;

  (v) Glaucoma, eg primary open angle glaucoma (POAG), juvenile onset primary open angle glaucoma, closed angle glaucoma, pseudoexfoliative glaucoma, anterior ischemic optic neuropathy (AION), ocular hypertension, Liger Reiger syndrome Normal-tension glaucoma, neovascular glaucoma, ocular inflammation and steroid glaucoma;

  (W) acute damage to ocular tissue and ocular trauma, such as post-traumatic glaucoma, traumatic optic neuropathy and central retinal artery occlusion (CRAO);

  (X) diabetes;

  (Y) diabetic neuropathy;

  (Z) skin-related symptoms such as psoriasis, eczema, burns, dermatitis, keloid formation, scar tissue formation and angiogenesis disorders;

  (aa) Derived from viral and bacterial infections such as sepsis, septic shock, gram-negative sepsis, malaria, meningitis, opportunistic infections, cachexia derived from infection or malignant disease, acquired immune deficiency syndrome (AIDS) Cachexia, AIDS, ARC (AIDS-related complex syndrome), pneumonia and herpes virus;

  (bb) muscle pain due to infection;

  (cc) influenza;

  (dd) Endotoxic shock;

  (ee) Toxic shock syndrome;

  (ff) autoimmune diseases such as graft-versus-host reaction and allograft rejection;

  (gg) bone resorption disease, such as osteoporosis;

  (Hh) multiple sclerosis;

  (ii) female reproductive system disorders, such as endometriosis;

  (Jj) pathological non-malignant symptoms such as hemangiomas (eg pediatric hemangiomas), nasopharyngeal hemangiofibromas, and avascular necrosis of bone;

  (Kk) benign and malignant tumor / neoplasm, eg cancer, eg colorectal cancer, brain cancer, bone cancer, epithelial cell derived neoplasm (epithelial cancer), eg basal cell carcinoma, adenocarcinoma, digestive organ cancer, eg tongue cancer , Mouth cancer, esophageal cancer, small intestine cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer such as squamous cell carcinoma and basal cell cancer, prostate cancer , Renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body;

  (Ll) leukemia;

  (Mm) lymphoma, eg B cell lymphoma;

  (nn) systemic lupus erythematosus (SLE);

  (oo) angiogenesis, eg neoplasm; and

  (Transition).

  Some embodiments of the present invention are alternatively (or additionally) directed to methods for the prevention or treatment of TNF-mediated symptoms. As used herein, the term “TNF-mediated condition” means that TNF releases another monokine, such as IL-1, IL-6, and / or IL-8, by control of TNF itself or By TNF, it refers to any symptom (especially any pathological symptom, ie disease or disorder) in which TNF plays a role. For example, IL-1 is a major component and its production or action is exacerbated or secreted in response to TNF and is therefore considered a disorder mediated by TNF.

  Examples of TNF-mediated symptoms include inflammation (eg rheumatoid arthritis), autoimmune disease, transplant rejection, multiple sclerosis, fibrotic disease, cancer, infectious diseases (eg malaria, mycobacterial infection, meninges) ), Fever, psoriasis, cardiovascular disease (eg post-ischemic reperfusion injury and congestive heart failure), pulmonary disease, bleeding, blood clots, hyperoxic alveolar damage, radiation damage, and acute phase responses such as infection And those associated with sepsis and those observed during shock (eg, septic shock and hemodynamic shock), cachexia and anorexia. Such symptoms also include infectious diseases. Examples of such infectious diseases include malaria, mycobacterial infection, and meningitis. Such infectious diseases include viral infections such as HIV, influenza viruses and herpes viruses such as type 1 herpes simplex virus (HSV-1), type 2 herpes simplex virus (HSV-2), cytomegalovirus (CMV). , Chickenpox-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies And rhinotracheitis and the like.

  Because TNF-β has close structural homology with TNF-α (also known as cachectin), and each induces a similar biological response and binds to the same cellular receptor, TNF- The synthesis of both α and TNF-β tends to be inhibited by the compounds of the present invention and is therefore collectively referred to herein as “TNF” unless otherwise noted.

  Some embodiments of the present invention are alternatively (or additionally) directed to methods for preventing or treating cyclooxygenase-2 mediated symptoms. As used herein, the term “cyclooxygenase-2 mediated condition” is any term that cyclooxygenase-2 plays a role by controlling cyclooxygenase-2 itself or by cyclooxygenase-2 releasing another factor. Refers to symptoms (particularly pathological symptoms, ie diseases and disorders). Numerous cyclooxygenase-2 mediated conditions are known in the art, examples include, for example, inflammation, and other cyclooxygenase mediated disorders listed by Carter et al. In US Pat. No. 6,271,253.

  In some embodiments of certain such items, the condition treated or prevented by the methods of the present invention comprises inflammation.

  In some embodiments of certain such articles, the condition treated or prevented by the methods of the present invention includes arthritis.

  In some embodiments of certain such items, the condition treated or prevented by the methods of the present invention comprises rheumatoid arthritis.

  In some embodiments of certain such items, the condition treated or prevented by the methods of the present invention includes asthma.

  In some embodiments of certain such articles, the condition treated or prevented by the methods of the present invention comprises coronary artery symptoms.

  In some embodiments of certain such items, the condition treated or prevented by the methods of the present invention comprises bone loss.

  In some embodiments of certain such articles, the condition treated or prevented by the methods of the present invention comprises B cell lymphoma.

  The phrase “preventing symptoms” means reducing (or delaying) the onset of symptoms in a mammal that has no symptoms but is predisposed to having symptoms. In contrast, the phrase “treating symptoms” means ameliorating, suppressing or eradicating existing symptoms.

  A wide variety of methods can be used alone or in combination with administering the pyrazole compounds described above. For example, the compounds may be administered orally, intravascularly (IV), intraperitoneally, subcutaneously, intramuscularly (IM), rectally by inhalation spray, or topically.

  Typically, the compounds described herein are administered in an amount effective to inhibit p38 kinase (particularly p38α), TNF (particularly TNF-α) and / or cyclooxygenase (particularly cyclooxygenase-2). Is done. The preferred total daily dose of the pyrazole compound (administered in a single dose or in divided doses) is typically about 0.01 to about 100 mg / kg, more preferably 0.1 to about 50 mg / kg, more preferably About 0.5 to about 30 mg / kg (ie, pyrazole compound g / kg body weight). Dosage unit compositions may contain such amounts or about that amount to assemble a daily dose. In many cases, administration of the compound is repeated multiple times a day (typically no more than 4 times). Multiple doses / day can typically be used to increase the total daily dose if desired.

  Factors affecting the preferred dosing regimen include patient type, age, weight, sex, diet and symptoms; severity of pathological symptoms; route of administration; pharmacological considerations, eg activity of the particular pyrazole compound used , Efficacy, pharmacokinetics and toxicological profile; whether a drug delivery system is utilized; and whether the pyrazole compound is administered as part of a drug combination. Thus, the actual dosing regime used will vary widely and may thus deviate from the preferred dosing regime described above.

  In addition to other conventional anti-inflammatory drugs such as steroids, the compounds of the present invention may be cyclooxygenase-2 inhibitors, non-steroidal anti-inflammatory drugs ("NSAIDs"), disease modifying anti-rheumatic drugs. Instead of drugs (“DMARD”), immunosuppressive drugs, 5-lipoxygenase inhibitors, leukotriene B4 (“LTB4”) antagonists and leukotriene A4 (“LTA4”) hydrolase inhibitors can be used for adjuvant therapy.

G. Formulation composition
Inclusion of compounds prepared according to the present invention The present invention relates to pharmaceutical compositions (or tautomers of compounds and pharmaceutically acceptable salts of tautomers) comprising substituted pyrazoles as described above (or "Pharmaceutical agents") and those compounds in one or more conventional non-toxic pharmaceutically acceptable carriers, diluents, wetting or suspending agents, vehicles and / or adjuvants (carriers, diluents, Wet or suspending agents, vehicles and adjuvants are sometimes also referred to herein collectively as “carrier substances”); and / or to methods of making pharmaceutical compositions comprising in combination with other active ingredients. It is done. The preferred composition depends on the method of administration. Pharmaceutical formulations are generally discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA: 1975), the description of which is incorporated herein by reference. . See also Liberman, HA, Lachman, L., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, NY, 1980, the description of which is hereby incorporated by reference). In embodiments, the pharmaceutical composition is manufactured in the form of a dosage unit containing a specific amount of the active ingredient, typically from about 0.1 to 1000 mg (and more typically from 7.0 to 350 mg). ) Substituted pyrazoles.

  Solid dosage forms for oral administration include, for example, hard or soft capsules, tablets, pills, powders and granules. In such solid dosage forms, the substituted pyrazole is usually combined with one or more adjuvants. When administered orally, substituted pyrazoles are lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid , Gelatin, gum arabic, sodium alginate, polyvinyl pyrrolidone and / or polyvinyl alcohol and can then be tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled release formulation, if they can be provided in a dispersion of a compound of the invention in hydroxypropyl methylcellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents such as sodium citrate, or carbonate or magnesium bicarbonate or calcium. Tablets and pills can additionally be prepared with enteric coatings.

  Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and inert diluents commonly used in the art (eg, water) and An elixir is mentioned. Such compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (eg sweetening agents) and / or flavoring agents.

  “Parenteral administration” includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections and infusions. Injectable preparations (eg, sterile injectable aqueous or oleaginous suspension) may be formulated according to methods known in the art using suitable dispersing agents, wetting agents, and / or suspending agents. Acceptable carrier materials include, for example, water, 1,3-butanediol, Ringer's solution, isotonic sodium chloride solution, nonirritating fixed oils (eg synthetic mono- or diglycerides), dextrose, mannitol, fatty acids (eg oleic acid) ), Dimethylacetamide, surfactants (eg ionic and non-ionic detergents) and / or polyethylene glycol (eg PEG 400).

  Formulations for parenteral administration can be prepared, for example, from sterile powders or granules having one or more carrier materials described for use in formulations for oral administration. The substituted pyrazole can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. The pH can be adjusted with a suitable acid, base or buffer as necessary.

  The compounds of the present invention are preferably about 0.075 to about 30% (w / w) (more preferably 0.2 to 20% (w / w), more preferably 0.4%) of a pharmaceutical composition used for topical or rectal administration. Make up ~ 15% (w / w).

  Suppositories for rectal administration are suitable non-irritating excipients, for example, compounds of the invention which are solid at normal temperature but liquid at rectal temperature and therefore melt in the rectum to release the drug. It can be prepared by mixing with an agent. Suitable excipients include, for example, cocoa butter, synthetic mono-, di- or triglycerides, fatty acids and / or polyethylene glycols.

  “Topical administration” includes transdermal administration, post-skin patch or iontophoresis device administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments and creams.

  When formulated in an ointment, the compounds of the invention may be used with, for example, paraffin or water-miscible ointment bases. When formulated in a cream, the active ingredient (s) can be formulated with an oil-in-water cream base, for example. Optionally, the aqueous phase of the cream base is, for example, at least about 30% (w / w) polyhydric alcohol, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. Can be included.

  Topical formulations may contain compounds which enhance the absorption or penetration of the active ingredient through the skin or other active areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

  When the compound of the invention is administered by a transdermal device, administration is accomplished using a reservoir and porous membrane type or solid matrix form patch. In either case, the active agent is continuously delivered from the reservoir or microcapsule through the membrane to the active agent permeable adhesive that is present adhering to the recipient's skin or mucosa. If the active agent is absorbed through the skin, control of the active agent and a predetermined flow rate is administered to the recipient. In the case of microcapsules, the encapsulant can also function as a membrane. Transdermal patches contain the compound in a suitable solvent system with an adhesive system, such as acrylic emulsions and polyester patches. The oily phase of the emulsions of the present invention can be composed of known ingredients in a known manner. While the phase may simply comprise an emulsifier, it may comprise, for example, a mixture of at least one emulsifier and fat or oil, or both fat and oil. Preferably a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both oil and fat. Both with or without stabilizer (s) make up a so-called emulsifying wax, and the wax together with oil and fat make up a so-called emulsifying ointment base, which is the oily dispersed phase of the cream formulation Form. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The selection of an appropriate oil or fat for the formulation is to achieve the desired cosmetic properties, assuming that the solubility of the active compound in most oils that would be used in a pharmaceutical emulsion formulation is very low. Based on Thus, the cream should preferably be a non-greasy, non-staining and washable material of suitable consistency to avoid leakage from test tubes or other containers. Linear or branched mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2 Formulations of ethylhexyl palmitate or branched chain esters can be used. These can be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used. Formulations suitable for topical administration to the eye also include eye drops wherein the compounds of the invention are dissolved or suspended in a suitable carrier, typically containing an aqueous solvent. The compound of the present invention is preferably at a concentration of about 0.5 to about 20% (w / w) (more preferably 0.5 to 10% (w / w), often more preferably about 1.5% (w / w)). Present in such formulations.

  Other carrier materials and modes of administration known in the pharmaceutical industry can also be used.

H. DEFINITIONS The term "alkyl" (alone or in combination with another term (s)) is typically from 1 to about 20 carbon atoms, more typically 1 to about 12 carbon atoms are further It means a linear or branched saturated hydrocarbyl substituent (ie, a substituent containing only carbon and hydrogen) that is typically 1 to about 8, more typically 1 to about 6. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and octyl.

  The term “alkenyl” (alone or in combination with another term (s)) typically has 2 to about 20 carbon atoms, more typically 2 to about 12 carbon atoms, and more typically It means a straight or branched hydrocarbyl substituent that is typically 2 to about 8, more typically 2 to about 6. Examples of such substituents include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl and decenyl. It is done.

  The term “alkynyl” (alone or in combination with another term (s)) contains one or more triple bonds, and typically has 2 to about 20 carbon atoms, more typically In particular, it means a straight or branched chain hydrocarbyl substituent having 2 to about 12, more typically 2 to about 8, and more typically 2 to about 6. Examples of such substituents include ethynyl, 1-propynyl, 2-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl and 1-pentynyl.

  The term “carbocyclyl” (alone or in combination with another term (s)) refers to 3 to 14 carbon ring atoms (“ring atoms” bonded together to form a singular number of cyclic substituents. Or a saturated cyclic (ie, “cycloalkyl”), partially saturated cyclic (ie, “cycloalkenyl”) or fully unsaturated (ie, “aryl”) hydrocarbyl substituent containing atoms that form multiple rings) . A carbocyclyl can be a single ring typically containing from 3 to 6 ring atoms. Examples of such single ring carbocyclyls include cyclopropanyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl. A carbocyclyl may alternatively be two or three rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl”), indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (“phenalenyl” ), Fluorenyl, decalinyl and norpinanyl.

  The term “cycloalkyl” (alone or in combination with another term (s)) refers to 3 to 14 carbon ring atoms, more typically 3 to about 12, more typically Means a saturated cyclic substituent containing from 3 to about 8 carbocyclic primitives. Cycloalkyls can be single carbocycles typically containing 3 to 6 carbon ring atoms. Examples of single ring cycloalkyl include cyclopropyl (or “cyclopropanyl”), cyclobutyl (or “cyclobutanyl”), cyclopentyl (or “cyclopentanyl”) and cyclohexyl (or “cyclohexanyl”). . Cycloalkyls can alternatively be 2 or 3 carbocycles fused together, such as decalinyl or norpinanyl.

  The term “cycloalkylalkyl” (alone or in combination with another term (s)) means an alkyl substituted with a cycloalkyl. Examples of such substituents include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

  The term “cycloalkenyl” (alone or in combination with another term (s)) means a partially unsaturated carbocyclyl substituent. Examples of such substituents include cyclobutenyl, cyclopentenyl and cyclohexenyl.

  The term “aryl” (alone or in combination with another term (s)) means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examples of aryl include phenyl, naphthalenyl and indenyl.

In some cases, the number of carbon atoms in the hydrocarbyl (eg, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, etc.) is prefixed with “C _x -C _y ” where x is in the substituent. Is the minimum number of carbon atoms, and y is the maximum number). Thus, for example, “C ₁ -C ₆ -alkyl” refers to an alkyl substituent containing from 1 to 6 carbon atoms. To further illustrate, C ₃ -C ₆ - cycloalkyl means a saturated carbocyclyl containing from 3 to 6 carbon ring atoms.

  The term “arylalkyl” (alone or in combination with another term (s)) means an alkyl substituted with an aryl.

The term “benzyl” (alone or in combination with another term (s)) means a methyl radical substituted with phenyl, ie the following structure:

The term “benzene” means the following structure:

  The term “hydrogen” (alone or in combination with another term (s)) means a hydrogen radical and may be represented as —H.

  The term “hydroxy” or “hydroxyl” (alone or in combination with another term (s)) means —OH.

  The term “hydroxyalkyl” (alone or in combination with another term (s)) means an alkyl substituted with one or more hydroxy.

The term “nitro” (alone or in combination with another term (s)) means —NO ₂ .

The term “cyano” (alone or in combination with another term (s)) means —CN, which is also represented as follows:

  The term “keto” (alone or in combination with another term (s)) means an oxo radical and may be represented as ═O.

The term “carboxy” or “carboxyl” (alone or in combination with another term (s)) means —C (O) —OH, which can also be represented as follows:

The term “amino” (alone or in combination with another term (s)) means —NH ₂ . The term “monosubstituted amino” (alone or in combination with another term (s)) means an amino substituent in which one of the hydrogen radicals is replaced by a non-hydrogen substituent. The term “disubstituted amino” (alone or in combination with another term (s)) means an amino substituent in which both hydrogen atoms are replaced by non-hydrogen substituents which may be the same or different. .

  The term "halogen" (alone or in combination with another term (s)) refers to a fluorine radical (represented as -F), a chlorine radical (represented as -Cl), a bromine radical (-Br Or iodine radical (represented as -I). Typically, fluorine radicals or chlorine radicals are preferred, and fluorine radicals are often particularly preferred.

  The prefix “halo” indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl means an alkyl substituent in which at least one hydrogen radical is replaced with a halogen radical. If there is more than one hydrogen substituted with a halogen, the halogen can be the same or different. Examples of haloalkyl include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, difluoroethyl, Mention may be made of pentafluoroethyl, difluoropropyl, dichloropropyl and heptafluoropropyl. To further illustrate, “haloalkoxy” means an alkoxy substituent in which at least one hydrogen radical is replaced by a halogen radical. Examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as “perfluoromethyloxy”) and 1,1,1-trifluoroethoxy. It is done. It should be recognized that when a substituent is substituted by more than one halogen radical, the halogen radicals may be the same or different (unless otherwise noted).

この用語は、水和カルボニル置換基、すなわち−Ｃ（ＯＨ）₂−も包含するよう意図される。 The term “carbonyl” (alone or in combination with another term (s)) means —C (O) —, which can also be represented as follows:

The term is also intended to encompass hydrated carbonyl substituents, ie, —C (OH) ₂ —.

The term “aminocarbonyl” (alone or in combination with another term (s)) means —C (O) —NH ₂ and may also be represented as follows:

  The term “oxy” (alone or in combination with another term (s)) means an ether substituent and may be represented as —O—.

The term “alkoxy” (alone or in combination with another term (s)) means an alkyl ether substituent, ie —O-alkyl. Examples of such substituents include methoxy (—O—CH ₃ ), ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

The term “alkylthio” (alone or in combination with another term (s)) means —S-alkyl. For example, “methylthio” is —S—CH ₃ . Other examples of alkylthio substituents include ethylthio, propylthio, butylthio and hexylthio.

その他のしばしば好ましいアルキルカルボニル置換基の例としては、メチルカルボニル、プロピルカルボニル、ブチルカルボニル、ペンチルカルボニルおよびヘキシルカルボニルが挙げられる。 The term “alkylcarbonyl” or “alkanoyl” (alone or in combination with another term (s)) means —C (O) -alkyl. For example, “ethylcarbonyl” can be represented as follows:

Examples of other often preferred alkylcarbonyl substituents include methylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl and hexylcarbonyl.

The term “aminoalkylcarbonyl” (alone or in combination with another term (s)) means —C (O) -alkyl-NH ₂ . For example, “aminomethylcarbonyl” can be represented as follows:

その他のしばしば好ましいアルコキシカルボニル置換基の例としては、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、ブトキシカルボニル、ペントキシカルボニルおよびヘキシルオキシカルボニルが挙げられる。 The term “alkoxycarbonyl” (alone or in combination with another term (s)) means —C (O) —O-alkyl. For example, “ethoxycarbonyl” may be represented as follows:

Examples of other often preferred alkoxycarbonyl substituents include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl and hexyloxycarbonyl.

同様に、「ヘテロシクリルカルボニル」（単独でまたは別の用語（単数または複数）と組合せた）という用語は、−Ｃ（Ｏ）−へテロシクリルを意味する。 The term “carbocyclylcarbonyl” (alone or in combination with another term (s)) means —C (O) -carbocyclyl. For example, “phenylcarbonyl” may be represented as follows:

Similarly, the term “heterocyclylcarbonyl” (alone or in combination with another term (s)) means —C (O) -heterocyclyl.

  The term “heterocyclylalkylcarbonyl” (alone or in combination with another term (s)) means —C (O) -alkyl-heterocyclyl.

The term “carbocyclyloxycarbonyl” (alone or in combination with another term (s)) means —C (O) —O-carbocyclyl. For example, “phenyloxycarbonyl” may be represented as follows:

The term “running thick alkoxycarbonyl” (alone or in combination with another term (s)) means —C (O) —O-alkyl-carbocyclyl. For example, “phenylethoxycarbonyl” may be represented as follows:

  The term “thio” or “thia” (alone or in combination with another term (s)) refers to a thiaether substituent, ie an ether substituent in which a divalent sulfur atom is present instead of an ether oxygen atom. Means. Such substituents can be represented as -S-. For example, “alkyl-thio-alkyl” means alkyl-S-alkyl.

  The term “thiol” (alone or in combination with another term (s)) means a sulfhydryl substituent and may be represented as —SH.

したがって、例えば「アルキル−スルホニル−アルキル」は、アルキル−Ｓ（Ｏ）₂−アルキルを意味する。典型的に好ましいアルキルスルホニル置換基の例としては、メチルスルホニル、エチルスルホニルおよびプロピルスルホニルが挙げられる。 The term “sulfonyl” (alone or in combination with another term (s)) means —S (O) ₂ —, which may be represented as follows:

Thus, for example, “alkyl-sulfonyl-alkyl” means alkyl-S (O) ₂ -alkyl. Examples of typically preferred alkylsulfonyl substituents include methylsulfonyl, ethylsulfonyl and propylsulfonyl.

The term “aminosulfonyl” (alone or in combination with another term (s)) means —S (O) ₂ —NH ₂ and may also be represented as follows:

したがって、例えば「アルキルスルフィニルアルキル」または「アルキルスルホキシドアルキル」は、アルキル−Ｓ（Ｏ）−アルキルを意味する。典型的に好ましいアルキルスルフィニル基としては、メチルスルフィニル、エチルスルフィニル、ブチルスルフィニルおよびヘキシルスルフィニルが挙げられる。 The term “sulfinyl” (alone or in combination with another term (s)) means —S (O) —, which may also be represented as follows:

Thus, for example, “alkylsulfinylalkyl” or “alkylsulfoxide alkyl” means alkyl-S (O) -alkyl. Typically preferred alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.

  The term “heterocyclyl” (alone or in combination with another term (s)) is a saturated cyclic containing 3 to 14 ring atoms (ie “heterocycloalkyl”), partially saturated (ie “ "Heterocycloalkenyl") or a fully unsaturated (ie, "heteroaryl") ring structure. At least one of the ring atoms is a heteroatom (ie oxygen, nitrogen or sulfur) and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen and sulfur.

  A heterocyclyl can be a single ring that typically contains 3 to 7 ring atoms, more typically 3 to 6, more typically 5 to 6 ring atoms. Examples of single ring heterocyclyl include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (also known as “thiofuranyl”), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl , Imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyloxyl, -Oxadiazolyl, 1,2,4-oxadiazolyl (also referred to as "azoxymil") ), 1,2,5-oxadiazolyl (also known as “furazanyl”) or 1,3,4-oxadiazolyl), oxatriazolyl (eg 1,2,3,4-oxatriazolyl) Or 1,2,3,5-oxatriazolyl), dioxazolyl (eg 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl or 1,3,4-dioxazolyl) , Oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl (eg, 1,2-pyranyl or 1,4-pyranyl), dihydropyranyl, pyridinyl (also known as “azinyl”), piperidinyl, diazinyl (eg, pyridazinyl (“1,2 -Also known as "-diazinyl"), pyrimidinyl ("1,3-diazinyl" or Also known as “pyrimidyl” or pyrazinyl (also known as “1,4-diazinyl”), piperazinyl, triazinyl (eg s-triazinyl (also known as “1,3,5-triazinyl”)) , As-triazinyl (also known as 1,2,4-triazinyl) and v-triazinyl (also known as “1,2,3-triazinyl”), oxazinyl (eg 1,2,3-oxazinyl) 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as “pentoxazolyl”), 1,2,6-oxazinyl or 1,4-oxazinyl), isoxazinyl (eg o-isoxazinyl or p -Isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (eg 1, 2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (eg 1,4,2-oxadiazinyl or 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl and diazepinyl It is done.

  The heterocyclyl can alternatively be two or three rings fused together, in which case at least one such ring contains a heteroatom (ie nitrogen, oxygen or sulfur) as a ring atom. Such substituents include, for example, indolizinyl, pyridinyl, pyranopyrrolyl, 4H-quinolidinyl, purinyl, naphthyridinyl, pyridopyridinyl (eg, pyrido [3,4-b] -pyridinyl, pyrido [3,2-b] -pyridinyl or pyrido [ 4,3-b] -pyridinyl) and pteridinyl. Other examples of fused ring heterocyclyl include benzo-fused heterocyclyl, such as indolyl, isoindolyl (also known as “isobenzazolyl” or “pseudoidindolyl”), indoleninyl (also known as “pseudoindolyl”), Isoindazolyl (also known as “benzpyrazolyl”), benzazinyl (also known as quinolinyl (also known as “1-benzazinyl”) or isoquinolinyl (also known as “2-benzazinyl”)), phthalazinyl, quinoxalinyl, quinazolinyl Benzodiazinyl (eg, cinnolinyl (also known as “1,2-benzodiazinyl”) or quinazolinyl (also known as “1,3-benzodiazinyl”)), benzopyranyl (eg, “chromanyl”) Or “isochromanyl”), benzothiopyranyl (also known as “thiochromanyl”), benzoxazolyl, indoxazinyl (also known as “benzisoxazolyl”), anthranilyl, benzodioxolyl, benzodioxanyl , Benzoxadiazolyl, benzofuranyl (also known as “coumaronyl”), isobenzofuranyl, benzothienyl (also known as “benzothiophenyl”, “thionaphthenyl” or “benzothiofuranyl”), iso Benzothienyl (also known as “isobenzothiophenyl”, “isothionaphthenyl” or “isobenzothiofuranyl”), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (eg 1, 3, -Benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl or 3,1,4-benzoxazinyl), benzisoxazinyl (eg 1,2-benzisoxazinyl or 1,4-benz Isoxazinyl), tetrahydroisoquinolinyl, carbazolyl, xanthenyl and acridinyl.

  The term “2-fused ring” heterocyclyl (alone or in combination with another term (s)) means a saturated, partially saturated or arylheterocyclyl containing two fused rings. Examples of 2-fused heterocyclyl include indolizinyl, pyridinyl, pyranopyrrolyl, 4H-quinolidinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, quinazolinyl, quinazolinyl, quinazolinyl, quinazolinyl Pyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxdiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotria Zolyl, benzoxazinyl, benzisoxazinyl and tetrahydroisoxone Riniru and the like.

  The term “heteroaryl” (alone or in combination with another term (s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms. Heteroaryl can be a single ring or a 2 or 3 fused ring. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1,2,3 Triazinyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl and isothiazolyl; 6 / 5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl and anthranilyl; and 6/6 membered fused rings such as 1,2-, 1,4-, 2,3- and 2,1-benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and 1,4 Benzoxazinyl and the like.

  The term “heterocyclylalkyl” (alone or in combination with another term (s)) means an alkyl substituted with a heterocyclyl.

  The term “heterocycloalkyl” (alone or in combination with another term (s)) means a fully saturated heterocyclyl.

In some preferred embodiments, the carbocyclyl or heterocyclyl is optionally halogen, hydroxy (—OH), cyano (—CN), nitro (—NO ₂ ), thiol (—SH), carboxy (—C (O) — OH), amino (—NH ₂ ), keto (═O), aminocarbonyl, alkyl, aminoalkyl, carboxyalkyl, alkylamino, alkylaminoalkyl, aminoalkylamino, alkylaminocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, Alkenyl, alkynyl, alkylthioalkyl, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, carboxyalkylthio, alkylcarbonyl (as "alkanoyl") Known), alkylcarbonyloxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxyalkylthio, alkoxycarbonylalkylthio, carboxyalkoxy, alkoxycarbonylalkoxy, carbocyclyl, carbocyclylaminocarbonyl, carbocyclylaminoalkyl, carbo Cycylalkoxy, carbocyclyloxyalkyl, carbocyclylalkoxyalkyl, carbocyclylthioalkyl, carbocyclylsulfinylalkyl, carbocyclylsulfonylalkyl, carbocyclylalkyl, carbocyclyloxy, carbocyclylthio, carbocyclyl Alkylthio, carbocyclylamino, carbocyclylalkylamino, carbocyclyl Rubonylaminocarbocyclylcarbonyl, carbocyclylalkyl, carbocyclylcarbonyloxy, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, carbocyclyloxyalkoxycarbocyclylcarbocyclylthioalkylthiocarbocyclyl, carbocyclylthioalkoxy Carbocyclyl, carbocyclyloxyalkylthiocarbocyclylheterocyclyl, heterocyclylaminocarbonyl, heterocyclylaminoalkyl, heterocyclylalkoxy, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthioalkyl, heterocyclylsulfinylalkyl, heterocyclylsulfonylalkyl, heterocyclylalkyl, heterocyclyloxy , Heterosic Rilthio, heterocyclylalkylthio, heterocyclylamino, heterocyclylalkylamino, heterocyclylcarbonylamino, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, heterocyclyloxycarbonyl, heterocyclylcarbonyloxy, heterocyclylalkoxycarbonyl, heterocyclyloxyalkoxyheterocyclyl, heterocyclylthioalkylthioheterocyclyl, heterocyclylthioalkoxyheterocyclyl Substituted with one or more substituents independently selected from the group consisting of heterocyclyloxyalkylthioheterocyclyl.

In some preferred embodiments, carbocyclyl or heterocyclyl optionally halogen, hydroxy, cyano, nitro, thiol, carboxy, amino, aminocarbonyl, C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, keto, carboxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylamino, C ₁ -C ₆ - alkylamino -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkylamino, C ₁ -C ₆ - alkylaminocarbonyl, aminocarbonyl -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxycarbonyl -C ₁ -C ₆ - alkyl, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, C ₁ -C ₆ - alkylthio -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylsulfinyl, C ₁ -C ₆ - alkylsulfinyl - ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylsulfonyl, C ₁ -C ₆ - alkylsulfonyl -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkylthio, carboxy -C ₁ -C ₆ - alkylthio , C _{1 ~C 6} - alkylcarbonyl, C _{1 ~C 6} - alkylcarbonyloxy, C _{1 ~C 6} - alkoxy, C _{1 ~C 6} - alkoxy -C ₁ -C ₆ - alkyl, C _{1 ~C 6} - alkoxycarbonyl, C _{1 ~C 6} - alkoxycarbonyl -C ₁ -C ₆ - alkoxy, C _{1 ~C 6} - alkoxy -C ₁ -C ₆ - alkylthio, C _{1 ~C 6} - alkoxycarbonyl -C ₁ -C ₆ - alkylthio, carboxy -C ₁ -C ₆ - alkoxy, C ₁ -C ₆ - alkoxycarbonyl -C ₁ -C ₆ - alkoxy, aryl, arylaminocarbonyl, arylamino -C ₁ ~ ₆ - alkyl, aryl -C ₁ -C ₆ - alkoxy, aryloxy -C ₁ -C ₆ - alkyl, aryl -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, arylthio -C ₁ -C ₆ - alkyl, arylsulfinyl -C ₁ -C ₆ - alkyl, arylsulfonyl -C ₁ -C ₆ - alkyl, aryl -C ₁ -C ₆ - alkyl, aryloxy, arylthio, aryl -C ₁ -C ₆ - alkylthio, arylamino, aryl -C ₁ -C ₆ - alkylamino, arylcarbonylamino, arylcarbonyl, aryl -C ₁ -C ₆ - alkylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, aryl -C ₁ -C ₆ - alkoxycarbonyl , aryloxy -C ₁ -C ₆ - alkoxy aryl, arylthio -C ₁ -C ₆ - alkyl thio aryl, arylthio -C ₁ -C ₆ - alkoxy aryl, arylthio -C ₁ -C ₆ - alkyl thio aryl, arylthio -C ₁ -C ₆ - alkoxy, aryloxy -C ₁ -C ₆ - alkylthio Aryl, cycloalkyl, cycloalkylaminocarbonyl, cycloalkylamino-C ₁ -C ₆ -alkyl, cycloalkyl-C ₁ -C ₆ -alkoxy, cycloalkyloxy-C ₁ -C ₆ -alkyl, cycloalkyl-C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, cycloalkylthio -C ₁ -C ₆ - alkyl, cycloalkyl alkylsulfinyl -C ₁ -C ₆ - alkyl, alkenyl cycloalkyl sulfonyl -C ₁ -C ₆ - alkyl cycloalkyl -C ₁ -C ₆ - alkyl, cycloalkyloxy, cycloalk Lucio, cyclo R kills -C ₁ -C ₆ - alkylthio, cycloalkylamino, cycloalkyl -C ₁ -C ₆ - alkylamino, cycloalkyl carbonyl amino, cycloalkyl carbonyl, cycloalkyl -C ₁ -C ₆ - alkylcarbonyl , cycloalkylcarbonyloxy, cycloalkyloxycarbonyl, cycloalkyl -C ₁ -C ₆ - alkoxycarbonyl, heteroaryl, heteroarylaminocarbonyl, heteroarylamino -C ₁ -C ₆ - alkyl, heteroaryl -C ₁ -C ₆ - alkoxy, heteroaryloxy -C ₁ -C ₆ - alkyl, heteroaryl -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, heteroarylthio -C ₁ -C ₆ - alkyl, heteroaryl arylsulfinyl -C ₁ -C ₆ - alkyl, Hetero arylsulfonyl -C ₁ -C ₆ - alkyl, heteroaryl -C ₁ -C ₆ - alkyl, heteroaryloxy, heteroarylthio, heteroaryl -C ₁ -C ₆ - alkylthio, heteroarylamino, heteroaryl -C ₁ -C ₆ - alkylamino, heteroarylcarbonylamino, heteroarylcarbonyl, heteroaryl -C ₁ -C ₆ - alkylcarbonyl, heteroaryloxycarbonyl, heteroarylcarbonyloxy, and heteroaryl -C ₁ -C ₆ - alkoxycarbonyl Substituted with one or more substituents independently selected from the group consisting of Here, any substitutable carbon is optionally substituted with one or more halogens. In addition, cycloalkyl, aryl and heteroaryl typically have from 3 to 6 ring atoms, more typically from 5 to 6 ring atoms.

  In some preferred embodiments, the carbocyclyl or heterocyclyl is halogen, hydroxy, carbonyl, keto, alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl (also known as “alkanoyl”), aryl, arylalkyl, arylalkoxy, aryl Optionally substituted with one or more substituents independently selected from the group consisting of alkoxyalkyl, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl and cycloalkylalkoxycarbonyl. The

In some preferred embodiments, carbocyclyl or heterocyclyl optionally halogen, hydroxy, carboxy, keto, C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy, C ₁ -C ₆ - alkoxy -C ₁ ~ C ₆ - alkyl, C ₁ -C ₆ - alkylcarbonyl, aryl, -C ₁ -C ₆ - alkyl, aryl -C ₁ -C ₆ - alkoxy, aryl -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, aryl -C ₁ -C ₆ - alkoxycarbonyl, cycloalkyl, cycloalkyl -C ₁ -C ₆ - alkyl, cycloalkyl -C ₁ -C ₆ - alkoxy, cycloalkyl -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl and cycloalkyl -C ₁ -C ₆ - alkoxy one member independently selected from the group consisting of carbonyl or Which is substituted by or more substituents. The alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl, aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl or arylalkoxycarbonyl substituent (s) can be further substituted with one or more halogens. Aryl or cycloalkyl typically has 3 to 6 ring atoms, more typically 5 to 6 ring atoms.

  In some preferred embodiments, the carbocyclyl or heterocyclyl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, amino, alkylthio, keto, and alkylamino. The

In some preferred embodiments, carbocyclyl or heterocyclyl optionally halogen, hydroxy, C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy, amino, C ₁ -C ₆ - alkylthio, keto and C ₁ ~ Substituted with up to three substituents independently selected from the group consisting of C ₆ -alkylamino.

  In some preferred embodiments, the carbocyclyl or heterocyclyl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy and amino.

In some preferred embodiments, carbocyclyl or heterocyclyl optionally, halogen, nitro, C ₁ -C ₆ - alkyl, halo -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy, halo -C ₁ ~ Substituted with up to three substituents independently selected from the group consisting of C ₆ -alkoxy and amino.

  In some preferred embodiments, the carbocyclyl or heterocyclyl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and haloalkoxy.

In some preferred embodiments, carbocyclyl or heterocyclyl optionally halogen, C ₁ -C ₆ - alkyl, halo -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy and halo -C ₁ -C ₆ Substituted with up to three substituents independently selected from the group consisting of alkoxy.

  A substituent is “substitutable” if it contains at least one carbon or nitrogen atom bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen and cyano do not fall within this definition.

  When a substituent is described as being “substituted”, a non-hydrogen radical is present in place of the hydrogen radical on the substituent carbon or nitrogen. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is present in place of a hydrogen radical on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro radical, and difluoroalkyl is alkyl substituted with two fluoro radicals. It should be appreciated that if there is more than one substitution on a substituent, each non-hydrogen radical may be the same or different (unless otherwise noted).

  Where a substituent is described as being “optionally substituted”, the substituent may be (1) unsubstituted or (2) substituted. Where a substituent is described as being optionally substituted with up to a specified number of non-hydrogen radicals, the substituent may be substituted with up to a specified number of non-hydrogen radicals or up to the maximum number on a substituent. Depending on the position, whichever is less, (1) not substituted or (2) can be substituted. Thus, for example, when a substituent is described as a heteroaryl optionally substituted with up to three non-hydrogen radicals, any heteroaryl having a substitutable position of less than 3 is defined as Optionally substituted with as many non-hydrogen radicals as there are. To illustrate, tetrazolyl (which has only one substitutable position) is optionally substituted with up to one non-hydrogen radical. To further illustrate, when the amino nitrogen is described as optionally substituted with up to two non-hydrogen radicals, the primary amino nitrogen is optionally substituted with up to two non-hydrogen radicals, while The secondary amino nitrogen is optionally substituted with only one non-hydrogen radical.

  The terms “substituent” and “radical” are interchangeable.

The prefix attached to the multi-component substituent applies only to the first component. To illustrate, the term “alkylcycloalkyl” contains two components: alkyl and cycloalkyl. Thus C ₁ -C ₆ - alkyl prefix relates cycloalkyl prefix C ₁ -C ₆ -, the alkyl components of alkylcycloalkyl means containing from 1 to 6 carbon atoms. The prefix C ₁ -C _6- does not describe a cycloalkyl component. To further illustrate, the prefix “halo” on haloalkoxyalkyl indicates that only the alkoxy component of the alkoxyalkyl substituent is substituted with one or more halogen radicals. Where halogen substitution occurs alternatively or additionally on an alkyl component, the substituent is described as “halogen substituted alkoxyalkyl” rather than “haloalkoxyalkyl”. Finally, where halogen substitution can only occur with alkyl components, the substituent is rather described as “alkoxyhaloalkyl”.

  When a substituent is described as “independently selected” from a group, each substituent is selected independently of the others. Thus, each substituent may be the same as or different from other substituent (s).

  The term “pharmaceutically acceptable” is used adjectively herein to mean that the modified noun is appropriate as a pharmaceutical product or as part of a pharmaceutical product.

  With respect to the use of the word “comprising” or “comprising (singular)” or “consisting of” in this patent (including claims), unless otherwise stated, The applicants note that they are used and clearly understood on the basis of being interpreted comprehensively rather than exclusively, and the applicants rather In interpreting this patent, including its scope, each of these terms is intended to be so explained.

  The following are definitions for various abbreviations:

  “Boc” is tert-butoxycarbonyl.

  “CEC” is 4-chlorobenzoyl chloride.

  “DBU” is 1,8-diazabicyclo [5.4.0] undec-7-ene.

  “DMAP” is dimethylaminopyridine.

  “DMF” is dimethylformamide.

  “DMSO” is dimethyl sulfoxide.

  “DSC” is differential scanning calorimetry.

  “Equiv” is equivalent.

  “H” or “hr” is one or more times.

  “HCl” is hydrochloric acid.

  “IPA” is isopropylpyr alcohol.

  “KF” is coulometric water measurement by the Karl Fischer method.

  “LDA” is diisopropylamine lithium.

  “LiHMDS” is lithium hexamethyldisil azide.

  “MCPBA” is 3-chloroperbenzoic acid.

  “Min” is one or more minutes.

  “MW” is molecular weight.

  “NaH” is sodium hydride.

  “NaOH” is sodium hydroxide.

  “NMP” means 1-methyl-2-pyrrolidinone (eg, “N-methylpyrrolidinone”, “1-methyl-2-pyrrolidone”, “N-methylpyrrolidone”, “N-methyl-2-pyrrolidinone”, “methyl” Also referred to as “pyrrolidinone” and “N-methyl-α-pyrrolidone”).

“N ₂ ” is nitrogen gas.

  “ROI” is an ignition residue.

  “TBuOK” is tert-butoxypotassium.

  “TFA” is trifluoroacetic acid.

  “THF” is tetrahydrofuran.

  “Ethanol 3A” is 95% absolute ethanol and 5% methanol () (HPLC grade).

EXAMPLES The following examples are merely illustrative and do not limit other parts of the disclosure in any way. These examples are directed to the preparation of certain preferred compounds (N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole) and ene. It is done. However, by applying the general principles illustrated in this example, as well as elsewhere in this specification, alone or in combination with existing knowledge in the art, others within the scope of Formula I above Can be prepared (and salts thereof). Existing knowledge in the industry includes, for example, PCT publication WO 00/31063 (the contents of which are incorporated herein by reference).

Example 1. Preparation of N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole

この反応は、凹湾曲撹拌器、窒素パージシステムおよび冷却器システムを装備した外被付49 L反応器中で実行した。反応器に、テトラヒドロフラン（「ＴＨＦ」）中の重炭酸ジ−ｔ−ブチル（１）（75％, 4.674 Kg, 16.06 mol）およびテトラヒドロフラン（5.50 Kg, 76.3 mol）を投入した。混合物を0℃に冷却後、0〜15℃の温度に内容物を保持しながら、イソニペコチン酸エチル（２）（2,500 Kg, 15.90 mol）を反応器に投入した。全てのイソニペコチン酸エチルを付加後、内容物を25℃に加温して、次にその温度で2時間撹拌した。次に混合物を0℃に冷却した。次に、バッチ温度が80℃に達するまで、真空蒸留によりＴＨＦを除去した。その後、内容物を25℃に冷却した。これは、琥珀色油の形態の生成物3.99 Kgを生じた。Ｂｏｃ保護化イソニペコチン酸エチル（３）の濃度は、96.3％（重量％）であった。

Part A. Preparation of ethyl N- (t-butoxycarbonyl) isonipecotate (3):

The reaction was carried out in a jacketed 49 L reactor equipped with a concave curve stirrer, nitrogen purge system and cooler system. The reactor was charged with di-tert-butyl bicarbonate (1) (75%, 4.674 Kg, 16.06 mol) and tetrahydrofuran (5.50 Kg, 76.3 mol) in tetrahydrofuran (“THF”). After cooling the mixture to 0 ° C., ethyl isonipecotate (2) (2,500 Kg, 15.90 mol) was charged into the reactor while maintaining the contents at a temperature of 0-15 ° C. After all the ethyl isonipecotate was added, the contents were warmed to 25 ° C. and then stirred at that temperature for 2 hours. The mixture was then cooled to 0 ° C. The THF was then removed by vacuum distillation until the batch temperature reached 80 ° C. The contents were then cooled to 25 ° C. This gave 3.99 Kg of product in the form of an amber oil. The concentration of Boc protected ethyl isonipecotate (3) was 96.3% (wt%).

この反応を、凹湾曲撹拌器、窒素パージシステム、内容物の下部の除去のための底バルブ、ならびにディーン・スタークトラップおよび冷却器システムを装備した同一の外被付49 L反応器中で実行した。反応器を先ず窒素でパージした。その後、ＴＨＦ中の20％ｔ−ブトキシドカリウム（21.06 Kg, 37.54 mol）をカニューレシステムを用いてＮ₂下で反応器に投入した。次にこの溶液を0℃に冷却し、次に0〜5℃に反応器内容物の温度を保持しながら、４−メチルピリミジン（４）（1.53 Kg, 16.27 mol）を反応器に投入した。その直後に、パートＡに示したように調製されたＢｏｃ保護化イソニペコチン酸エチル（３）（3.99 Kg, 15.51 mol）を、0〜5℃に反応器内容物の温度を保持し続けながら、正味30分間に亘って投入した。その後、5℃に保持しながら、反応器内容物を3時間撹拌した。反応器内容物の温度を10℃に加温して、次にその温度を1時間保持した。その後、反応混合物を30℃より低い温度に保持しながら、33％酢酸水溶液（6.71Kg, 36.88 mol）を反応混合物に投入した。その結果生じた混合物を30分間撹拌後、それを30分間放置した。次に水性層を分離した。その後、塩化アンモニウム溶液（2.96 Kg, 3.87 mol）を反応器に投入した。その結果生じた混合物を30分間撹拌した。混合物を30分間放置した後、水性層を分離させた。蒸留装置を用いて、温度が60〜65℃に達するまで、真空下でバッチ温度を徐々に上げることにより、有機残存層からＴＨＦを除去した。最終濃縮物は琥珀色油の形態であった。この油およびトルエン（12.22 Kg, 132.6 mol）を反応器中で併合し、その結果生じた混合物を室温で15分間撹拌した。その後、水（4.01 Kg, 222.5 mol）を反応器に付加し、室温でさらに30分間、撹拌を継続した。反応器内容物を60分間放置した。次に水性層を分離した。次に上部層（すなわち有機層）をそのまま用いて、パートＣのヒドラゾンを調製した。

Part B. Preparation of N- (t-butoxycarbonyl) -1- (4-piperidyl) -2- (4-pyrimidyl) -1-ethanone (5):

This reaction was carried out in the same jacketed 49 L reactor equipped with a concave curved stirrer, nitrogen purge system, bottom valve for removal of the bottom of the contents, and Dean-Stark trap and cooler system. . The reactor was first purged with nitrogen. Then 20% potassium t-butoxide in THF (21.06 Kg, 37.54 mol) was charged into the reactor under N ₂ using a cannula system. The solution was then cooled to 0 ° C. and then 4-methylpyrimidine (4) (1.53 Kg, 16.27 mol) was charged to the reactor while maintaining the temperature of the reactor contents at 0-5 ° C. Immediately thereafter, Boc-protected ethyl isonipecotate (3) (3.99 Kg, 15.51 mol), prepared as shown in Part A, was added to the net while maintaining the temperature of the reactor contents at 0-5 ° C. Added over 30 minutes. The reactor contents were then stirred for 3 hours while maintaining at 5 ° C. The temperature of the reactor contents was warmed to 10 ° C. and then that temperature was held for 1 hour. Thereafter, 33% aqueous acetic acid (6.71 Kg, 36.88 mol) was added to the reaction mixture while maintaining the reaction mixture at a temperature lower than 30 ° C. The resulting mixture was stirred for 30 minutes before it was left for 30 minutes. The aqueous layer was then separated. Thereafter, an ammonium chloride solution (2.96 Kg, 3.87 mol) was charged into the reactor. The resulting mixture was stirred for 30 minutes. The mixture was left for 30 minutes before the aqueous layer was separated. Using a distillation apparatus, THF was removed from the organic residual layer by gradually increasing the batch temperature under vacuum until the temperature reached 60-65 ° C. The final concentrate was in the form of amber oil. This oil and toluene (12.22 Kg, 132.6 mol) were combined in the reactor and the resulting mixture was stirred at room temperature for 15 minutes. Then water (4.01 Kg, 222.5 mol) was added to the reactor and stirring was continued for an additional 30 minutes at room temperature. The reactor contents were left for 60 minutes. The aqueous layer was then separated. The upper layer (ie, organic layer) was then used as is to prepare Part C hydrazone.

トルエンスルホニルヒドラジド（６）（2.6 Kg, 13.96 mol）を、同一反応器中でパートＢからの反応混合物と併合した。その結果生じた混合物を撹拌しながら70℃に加熱し、この温度を2時間保持した。次に、ディーン・スターク真空トラップを用いて減圧（200 torr）下で1時間、70℃で反応混合物を還流した。その後、混合物を1.5時間に亘って0℃に冷却し、次に少なくとも12時間0℃に保持した。その結果生じた固体を、フィルター（4ミクロンフィルター布を使用）を用いて収集した。次に湿潤ケークをトルエン（3.79 Kg, 41.13 mol, 0〜5℃）で、その後酢酸エチル（3.95 Kg, 44.83 mol, 0〜5℃）で洗浄した。ケークをフィルター上で2時間乾燥後、次に少なくとも4時間、40℃の真空オーブンに移した。これは、淡黄色油5.15 Kg（70％）を生じた。ヒドラゾン（７）の濃度は99.2％(重量％)であった。

Part C. Preparation of N- (t-butoxycarbonyl) -1- (4-piperidyl) -2- (4-pyrimidyl) -1-ethanone p-toluenesulfonylhydrazone (7):

Toluenesulfonyl hydrazide (6) (2.6 Kg, 13.96 mol) was combined with the reaction mixture from Part B in the same reactor. The resulting mixture was heated to 70 ° C. with stirring and this temperature was maintained for 2 hours. The reaction mixture was then refluxed at 70 ° C. using a Dean-Stark vacuum trap for 1 hour under reduced pressure (200 torr). The mixture was then cooled to 0 ° C. over 1.5 hours and then held at 0 ° C. for at least 12 hours. The resulting solid was collected using a filter (using a 4 micron filter cloth). The wet cake was then washed with toluene (3.79 Kg, 41.13 mol, 0-5 ° C) followed by ethyl acetate (3.95 Kg, 44.83 mol, 0-5 ° C). The cake was dried on the filter for 2 hours and then transferred to a 40 ° C. vacuum oven for at least 4 hours. This yielded 5.15 Kg (70%) of a pale yellow oil. The concentration of hydrazone (7) was 99.2% (wt%).

この反応を、凹湾曲撹拌器、定量ポンプ、窒素パージシステムおよび冷却器システムを装備した同一の外被付49 L反応器中で実行した。反応器を先ず室温で窒素でパージした。次に清浄乾燥反応器に、パートＣに示したように調製したヒドラゾン（７）（2.77 Kg, 5.85 mol）、ジメチルアミノピリジン（「ＤＭＡＰ」）（0.0715 Kg, 0.585 mol）、テトラヒドロフラン（ 12.47 Kg, 173.04 mol）およびトリエチルアミン（0.829 Kg, 8.19 mol）を投入した。次に、内部温度を40℃未満に保持するような速度でポンプを用いて、20分間に亘って、塩化４−クロロベンゾイル（８）（「ＣＢＣ」）（1.28 Kg, 7.31 mol）を反応器に付加した。内容物が濃黄色に変わり、沈殿物を生じた。塩化４−クロロベンジルの付加後、反応混合物を30分間に亘って65℃に加熱し、次にその温度を5時間保持した。その後、混合物の温度を室温に下げて、水(2.77 Kg, 153.7 mol)を付加した。その結果生じた混合物を0.5時間撹拌した。その後、有機および水性相を分離させて、水性相を反応器の底から除去した。残りの有機層に、22％塩化アンモニウム水溶液（4.62 L）を付加した。その結果生じた混合物を0.5時間撹拌した。撹拌を停止し、有機および水性相を分離させた。水性相を反応器の底から除去した。次にＩＰＡ−水混合物（1:1（vol:vol）；22.16 L）を残りの有機化合物に2時間に亘って付加した。その後、その結果生じた混合物を5時間撹拌した。固体を濾過（4ミクロンフィルター布）し、ＩＰＡ−水混合物（1:1（vol:vol）；7.39 L）で洗浄し、フィルター上で2時間乾燥した。湿潤ケークを6時間80℃の真空オーブン(室内真空機)に移した。これは、2.85 Kg（84.6％）の固体を生じた。保護化ピラゾール中間体（９）の濃度は、99.0％(重量％)であった。

Part D. tert-Butyl 4- {5- (4-chlorophenyl) -1-[(4-methylphenyl) sulfonyl] -4-pyrimidin-4-yl-1H-pyrazol-3-yl} piperidine-1-carboxylate (9 Preparation of:

This reaction was carried out in the same jacketed 49 L reactor equipped with a concave stirrer, metering pump, nitrogen purge system and cooler system. The reactor was first purged with nitrogen at room temperature. The clean dry reactor was then charged with hydrazone (7) (2.77 Kg, 5.85 mol), dimethylaminopyridine ("DMAP") (0.0715 Kg, 0.585 mol), tetrahydrofuran (12.47 Kg, prepared as shown in Part C). 173.04 mol) and triethylamine (0.829 Kg, 8.19 mol) were added. The reactor is then charged with 4-chlorobenzoyl chloride (8) (“CBC”) (1.28 Kg, 7.31 mol) over a period of 20 minutes using a pump at a rate to keep the internal temperature below 40 ° C. Added to. The content turned dark yellow and a precipitate formed. After the addition of 4-chlorobenzyl chloride, the reaction mixture was heated to 65 ° C. over 30 minutes and then held at that temperature for 5 hours. Then the temperature of the mixture was lowered to room temperature and water (2.77 Kg, 153.7 mol) was added. The resulting mixture was stirred for 0.5 hour. The organic and aqueous phases were then separated and the aqueous phase was removed from the bottom of the reactor. To the remaining organic layer, 22% aqueous ammonium chloride solution (4.62 L) was added. The resulting mixture was stirred for 0.5 hour. Stirring was stopped and the organic and aqueous phases were allowed to separate. The aqueous phase was removed from the bottom of the reactor. The IPA-water mixture (1: 1 (vol: vol); 22.16 L) was then added to the remaining organic compounds over 2 hours. The resulting mixture was then stirred for 5 hours. The solid was filtered (4 micron filter cloth), washed with IPA-water mixture (1: 1 (vol: vol); 7.39 L) and dried on the filter for 2 hours. The wet cake was transferred to a vacuum oven (indoor vacuum machine) at 80 ° C. for 6 hours. This yielded 2.85 Kg (84.6%) solid. The concentration of the protected pyrazole intermediate (9) was 99.0% (wt%).

以下の考察は、この反応の2つの変法を記載する。 Part E. Preparation of 5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole (10):

The following discussion describes two variations of this reaction.

A. First Variant In the first variant, the above reaction was carried out in the same jacketed 49 L reactor equipped with a concave curve stirrer, nitrogen purge and metering pump. The reactor was charged with the protected pyrazole intermediate (9) (5.0 Kg, 8.42 mol) and toluene (10.0 Kg, 108.5 mol) prepared as shown in Part D. After stirring was started, 37% HCl (6.64 Kg, 67.4 mol) was added via a pump over 15 minutes. Immediately thereafter, gas evolution and a temperature increase from 22.2 ° C to 28.4 ° C were observed. Two phases appeared within 10 minutes. The temperature was held at 20 ° C. for 1.0 hour. Water (20 Kg, 1110 mol) was then added and the resulting mixture was stirred for 20 minutes. The organic and aqueous phases were then separated and the aqueous phase was returned to the reactor. Next, 6 N NaOH (10.0 Kg, 60.2 mol) was further charged to the reactor through a pump over 30 minutes. This increased the pH to 12 and produced a white / off-white slurry. The mixture was heated to 75 ° C. for 30 minutes and then held at that temperature for an additional 2 hours. The mixture was then cooled to 25 ° C. The solid was filtered through a 4 micron filter cloth, washed with deionized water (3 × 15 Kg) and air dried for 45 minutes, ie until constant weight (LOD <50%) was observed. The resulting cake was introduced into the reactor along with acetonitrile (15 Kg). The mixture was heated to reflux and then reflux was held for 1 hour. The solid was filtered through a 4 micron filter cloth, washed with acetonitrile (15 Kg) and dried in a vacuum oven at 85 ° C. for 12 hours (LOD <1%). This gave a faint off-white solid, 2.64 Kg. The concentration of 5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole was higher than 97% (wt%). No single impurity was present at> 1% (wt%). The ignition residue (“ROI”) was <1%, and the coulometric water measurement by the Karl Fischer method (“KF”) was also <1%.

B. Second Variant In the second variant , the above reaction was similarly carried out in the same jacketed 49 L reactor equipped with a concave curve stirrer, nitrogen purge and metering pump. The reactor was charged with the protected pyrazole intermediate (9) (5.0 Kg, 8.42 mol) and toluene (10.0 Kg, 108.5 mol) prepared as shown in Part D. After stirring was started, 37% HCl (6.64 Kg, 67.4 mol) was added over 16 minutes. A temperature increase from 20 ° C. to 28 ° C. was observed during the addition. The temperature of the mixture was then raised to 70 ° C. over 30 minutes (1.5 ° C./min) and held at 70 ° C. for 2 hours. The mixture was then cooled to 23 ° C. over 1 hour. After adding water (20 L), the mixture was stirred for 30 minutes. Agitation was then stopped and the phases were allowed to separate for 57 minutes. The bottom phase (ie the aqueous phase containing the product) was removed from the reactor. After removing the upper phase (ie organic phase), the reactor was rinsed with toluene and then with water to remove the residue. The aqueous phase containing the product was then returned to the reactor. The reactor was then charged with additional 6 N NaOH (10.0 Kg, 54.74 mol, 6.5 equivalents) over 27 minutes. The final pH observed was 12.25. The reaction mixture was then heated to 75 ° C. over 30 minutes and held at that temperature for 2 hours. The slurry was then cooled to 25 ° C. at rest. The product (in solid form) was collected by filtration using a pressure filter and washed on the filter with water (2 × 15 L). The final pH of the rinse solution was 7.5. The cake was pulled and dried for 60 minutes. This provided a wet cake with 19.4% LOD. The wet cake was returned to the reactor with acetonitrile (15.0 Kg, 19.1 L). The resulting mixture was heated to reflux (82 ° C.) and held at that temperature for 2 hours and 29 minutes. The slurry was then cooled to 5 ° C. and held at that temperature for 30 minutes. The resulting product was filtered and then dried by pulling the filter until the mother languor did not come out of the filter. The cake was washed with acetonitrile (18 L) and then pulled dry for 2 hours. The wet cake (LOD 12.2%) was transferred to a 85 ° C. vacuum dryer and dried for 16 hours and 20 minutes (although a time of 6-12 hours was considered sufficient). This provided 2.64 Kg with an isolated yield of 92.2%.

以下の考察は、この反応の3つの変法を記載する。 Part F. Preparation of NMP (12) solvate of N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole:

The following discussion describes three variations of this reaction.

A. First Variant This reaction was carried out in the same jacketed 0.1 L reactor equipped with stirrer, nitrogen purge, thermocouple and cooler. The reactor was charged with 5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole (10) (10 g, 0.029 mol) prepared as shown in Part E; -2-pyrrolidinone (20 g, 0.20 mol); butyl glycolate (11) (9.7 g, 0.073 mol) and 1,8-diazabicyclo [5.4.0] undec-7-ene ("DBU") (0.45 g, 0.0029 mol). After the start of stirring, the mixture was heated to about 110 ° C. and then held at that temperature for 3 hours. At that time, HPLC determined that the conversion of starting material to product had ceased (ie, <3 area% starting material remained). The reactor contents were then cooled to 25 ° C. over 1 hour. Ethanol 3A (1.74 g, 0.038 mol) was then charged into the reactor. The resulting mixture was held at 25 ° C for an additional hour and then cooled to 0 ° C for an additional 30 minutes. This temperature was held for another 2 hours. The solid is collected by filtration through a 4 micron filter cloth, washed with NMP (2 × 18 g) and air dried on the filter to yield the NMP solvate of the desired product, which is differentially scanned by calorimetry. Analysis by measurement (“DSC”). The solid was introduced into the reactor with 100 mL of ethanol. The resulting mixture was then heated to reflux and maintained at reflux for 4 hours. The mixture was then cooled to 15 ° C. over 3 hours. The product was then isolated by filtration through a 4 micron filter cloth, washed with ethanol 3A (2 × 33 g) (using displacement wash) and air dried on the filter. This resulted in 9.0 g (78% yield) of white / off-white / yellow crystals (HPLC weight%> 98%).

B. Second Variant In the second variant , the reaction was carried out in a jacketed 49 L reactor equipped with a concave curved stirrer, nitrogen purge and metering pump. The reactor was charged with 5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole (10) (1.9 Kg, 5.6 mol) and 1- 1 prepared as shown in Part E. Methyl-2-pyrrolidinone (3.8 Kg, 38.3 mol) was added. Stirring was started at 75 rpm, and the mixture was allowed to stir for 6 minutes. While continuing to stir the contents, the reactor was further charged with butyl glycolate (11) (1.85 Kg, 14 mol; added via addition funnel) And DBU (85.12 g, 0.54 mol) was added. The mixture was then heated to 110 ° C. over 23 minutes and then held at that temperature for 3 hours. A sample taken 15 minutes after the 110 ° C. temperature was achieved showed 87.2% conversion of 5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole (10), A sample taken 60 minutes after the temperature was reached showed 98.7% conversion of 5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole (10) and a temperature of 110 ° C. A sample taken 120 minutes after the was achieved showed 99.7% conversion of 5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole (10). After heating, the reaction mixture was cooled to about 25 ° C. over 1 hour 5 minutes (final baffle temperature was 28.5 ° C. while the bottom content was 22.2 ° C.). A sample was taken and then the reactor was charged with ethanol 3A (12.35 Kg, 268 mol) over 55 minutes. A sample was taken after ethanol was added. The mixture was then stirred for 65 minutes. A sample taken after the first 30 minutes of stirring was N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole product (12). A sample taken after 60 minutes of stirring showed that 2.8% remained in solution and was N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4-pyrimidinyl) -3- ( It was shown that 3.4% of the 4-chlorophenyl) pyrazole product (12) was present in the solution. The mixture was then heated to reflux for 1 hour and 2 minutes and then held at reflux for 4 hours. Supernatant and solid samples were taken every 30 minutes. After refluxing for 4 hours, the mixture was cooled to 5 ° C. at a rate of 0.25 ° C./min and then kept at that temperature overnight. The resulting product was filtered to give 17.46 Kg of filtrate. The cake was washed with ethanol 3A (2 × 3.14 Kg (68.3 mol)). The wash cake was then pulled to LOD = 0.67% and dried. The resulting amount of wet cake was 2.00 Kg (non-assay adjusted molar yield 89.7%). The NMP concentration in the wet cake was determined to be 518 ppm using gas chromatography (“GC”). The NMP concentration in the wet cake using the GC method with solid phase microextraction (“SPME”) was 580 ppm.

  A portion of the wet cake (1.0 Kg, 2.51 mol) was then combined with ethanol 3A (9.0 Kg,, 11.38 L, 196 mol) by vacuum in the same reactor. Agitation was set at 80 RPM. The mixture was heated to reflux (ie 78-80 ° C.) for 33 minutes and then maintained at reflux for 3 hours 10 minutes. Samples were taken after the first 1 hour 10 minutes, the first 2 hours 10 minutes, and at the end of 3 hours 10 minutes. The mixture was then cooled to 5 ° C. over 3 hours and 10 minutes and held at 5 ° C. overnight (ie, about 16 hours and 50 minutes). Samples were taken during the temperature drop period. The solid was filtered using a pressure filter and a sample was taken from the mother liquor. The amount of mother liquor collected was 8.68 Kg. The cake was washed with ethanol 3A (2 × 3.14 Kg (68.3 mol)) (sample was taken after each wash). The cake was then pulled dry for 1-2 hours at LOD = 0.31%. This resulted in a wet cake of 0.892 Kg (non-calibrated adjusted molar yield 89.6%). The total impurity in the cake is determined to be 0.46% (wt%), NMP is present at a concentration of 0.01% (wt%), and 5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4 -Chlorophenyl) pyrazole (10) was present at a concentration of 0.01% (wt%).

C. Third Variation In the third variation , the reaction was carried out in a jacketed 0.1 L reactor equipped with a stirrer, nitrogen purge, thermocouple and cooler. The reactor was charged with 5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole (10) (1.9 Kg, 5.6 mol, LOC = 0.40%, prepared as shown in Part E. ) And 1-methyl-2-pyrrolidinone (3.8 Kg, 38.3 mol). Stirring was started at 75 rpm and the reactor was further stirred with butyl glycolate (11) (1.85 Kg, 14 mol), added via addition funnel) and DBU (85.08 g, 0.56 mol) while stirring the contents. ). The mixture was then heated to 110 ° C. over 50 minutes and then held at that temperature for 3 hours and 25 minutes. A sample taken 15 minutes after the 110 ° C. temperature was reached showed 89.8% conversion of 5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole (10), A sample taken 60 minutes after the temperature was reached showed 99.1% conversion of 5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole (10) and a temperature of 110 ° C. A sample taken 180 minutes after was achieved showed 99.6% conversion of 5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole (10). Over 2 hours and 20 minutes, the reaction mixture was cooled to about 40 ° C. and a sample was taken. The reactor was then charged with ethanol 3A (0.76 Kg, 16.5 mol) over 23 minutes. A solid sample was taken after ethanol addition. The mixture was heated to reflux for 1 hour and 20 minutes and then maintained at reflux for 4 hours. Supernatant and solid samples were taken every 60 minutes. After refluxing, the mixture was cooled to 5 ° C. at a rate of 0.25 ° C./min and then kept at that temperature overnight. Solid samples and supernatants were collected. The mixture was then filtered to give 3.54 Kg of filtrate (sample of filtrate was collected). The cake was washed with methyl t-butyl ether (“MTBE”, 2 × 3.14 Kg (35.6 mol), a sample of MTBE collected after each wash). The wash cake was then pulled dry for 1 hour 15 minutes (LOD = 0.47%). This produced a wet cake of 2.56 Kg. The non-assay adjusted molar yield was 92.1%. The NMP concentration in the wet cake was determined to be 518 ppm using gas chromatography. The NMP concentration in the wet cake using the GC method with SPME was 580 ppm. The wet cake was then processed using two alternative approaches:

i. First Alternative Wet Cake Treatment A portion of the wet cake prepared above (1.2 Kg, LOD-0.47%) was charged to the same reactor with ethanol 3A (9.0 Kg, 11.38 mol) by vacuum. This resulted in a thick slurry. The stirrer speed was set at 95 RPM. The slurry was heated to reflux (ie 78-80 ° C.) for 16 hours and then maintained at reflux for 5 hours. Samples were taken when the mixture first reached reflux temperature after 102 hours, 162 hours, 186 hours, and 251 minutes. The mixture was then cooled to 5 ° C. over 2 hours 46 minutes and held at that temperature overnight (ie about 11 hours 59 minutes). The product was filtered using a pressure filter to produce 8.50 Kg of mother liquor (sample of mother liquor was collected). The cake was washed with ethanol (2 x 1.60 Kg) (sample taken after each wash). The cake was then pulled and dried for 2-3 hours. This resulted in a 1.07 Kg wet cake (LOD = 18.0%). After sample collection, the wet cake was then dried in a vacuum dryer at 50 ° C. for approximately the weekend period. This resulted in a wet cake of 0.894 Kg (LOD = 0.51%) with an untested adjusted molar yield of 93.0%. The total impurity in the cake is determined to be 0.45% (wt%), NMP is present at a concentration of 0.01% (wt%), and 5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4 -Chlorophenyl) pyrazole (10) was present at a concentration of 0.01% (wt%).

ii. Second Alternative Wet Cake Treatment A second portion (4 g) of the wet cake was charged into a nitrogen purged 100 ml jacketed vessel equipped with a cooling device and an overhead stirrer. Ethanol 3A (34.2 g ethanol and 1.8 g methanol) and DBU (0.15 g) were premixed and then charged to the reactor while stirring the contents at 250 RPM. Stirring was continued for 1 hour at room temperature. The contents were then heated to reflux for 1 hour and then cooled to 0 ° C. over 3 hours. The next day, the solid was filtered and washed with ethanol 3A. The resulting cake was pulled and dried overnight in a room vacuum. The solid was then placed in a vacuum oven and heated to about 50 ° C. for several more hours.

窒素噴水装置に連結された管アダプターおよび磁気撹拌棒を装備した10 mL一首丸底フラスコに、Ｎ−（２−ヒドロキシアセチル）−５−（４−ピペリジル）−４（４−ピリミジニル）−３−（４−クロロフェニル）ピラゾール（0.398 g, 1.0 mmol）およびエタノール3.0 mLを投入した。次に塩化水素をエタノール中の1.0 M溶液（1.25 mL, 1.25 mmol）として付加した。その結果生じた懸濁液を室温で1時間撹拌し、次に加熱、還流した。熱溶液を濾過して、少量の不溶性物質を除去した。次に濾液を室温で2時間撹拌した。生成された懸濁液を次に氷水浴中で冷却し、さらに2時間撹拌した。結晶の懸濁液を濾過し、収集固体を油ポンプ真空下で40℃で2時間乾燥し、0.381 gのＨＣｌ塩を黄色結晶固体として得た。塩は、以下の特徴を有した：

顕微分析：（Ｃ₂₀Ｈ₂₀ＣｌＮ₅Ｏ₂）・ＨＣｌ・0.2（ＥｔＯＨ）に関する計算値：Ｃ、55.24；Ｈ、5.04；Ｎ、15.79。実測値：Ｃ、54.97；Ｈ、5.04；Ｎ、15.72。 Example 2 Preparation of HCl salt of N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole

To a 10 mL one-necked round bottom flask equipped with a tube adapter connected to a nitrogen fountain device and a magnetic stir bar, N- (2-hydroxyacetyl) -5- (4-piperidyl) -4 (4-pyrimidinyl) -3 -(4-Chlorophenyl) pyrazole (0.398 g, 1.0 mmol) and ethanol (3.0 mL) were added. Hydrogen chloride was then added as a 1.0 M solution in ethanol (1.25 mL, 1.25 mmol). The resulting suspension was stirred at room temperature for 1 hour and then heated to reflux. The hot solution was filtered to remove a small amount of insoluble material. The filtrate was then stirred at room temperature for 2 hours. The resulting suspension was then cooled in an ice-water bath and stirred for an additional 2 hours. The crystalline suspension was filtered and the collected solid was dried under oil pump vacuum at 40 ° C. for 2 hours to give 0.381 g of HCl salt as a yellow crystalline solid. The salt had the following characteristics:

Microscopic _{analysis: (C 20 H 20 ClN 5} O 2) · HCl · 0.2 (EtOH) Calculated for: C, 55.24; H, 5.04 ; N, 15.79. Found: C, 54.97; H, 5.04; N, 15.72.

  The above detailed description of the preferred embodiments is intended to enable the present invention to be adapted and applied in numerous ways to those skilled in the art, as they may be most appropriate to the requirements of practical use. It is intended only for those skilled in the art to be familiar with the principles and their practical applications. Therefore, the present invention is not limited to the above-described embodiments, and various modifications can be made.

Claims (158)

A method for producing a substituted pyrazole, a tautomer of a substituted pyrazole, or a salt of a substituted pyrazole or a tautomer, wherein the substituted pyrazole has the following formula (I):

And the method comprises the following:
Producing a mixture by a method comprising introducing hydrazone and optionally substituted benzoyl halide into the reactor; and
Heating the mixture to a temperature higher than 50 ° C., and the hydrazone has the following formula (II):

And an optionally substituted benzoyl halide has the following formula (III):

And R ^B is halogen; and R ^3A , R ^3B and R ^3C are independently hydrogen, halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino , Selected from the group consisting of alkoxy and alkoxyalkyl, wherein
Any carbon of alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy or alkoxyalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and cyano. ;
One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═C (R ⁴ ) —;
One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═N—;
^{Three of} Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are independently selected from the group consisting of ═C (H) — and ═N—;
R ⁴ is hydrogen, halogen, cyano, hydroxy, thiol, carboxy, nitro, alkyl, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxy , Carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylthio, carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy, carbocyclylheterocyclyl, heterocyclylalkyl, heterocyclyloxy, Heterocyclylalkoxy, amino, aminoalkyl, alkylamino, alkenylamino, alkini Amino, carbocyclylamino, heterocyclylamino, aminocarbonyl, alkoxy, alkoxyalkyl, alkenyloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, carbocyclyloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxycarboxy Kurylamino, alkoxycarbocyclylalkylamino, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylamino, alkylaminoalkylamino, carbocyclylalkylamino, alkylaminoalkylaminoalkylamino, alkylheterocyclyl Amino, heterocyclylalkylamino, alkylhe Selected from the group consisting of telocyclylalkylamino, carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, alkylaminocarbonyl, alkylcarbonylamino, hydrazinyl, alkylhydrazinyl and carbocyclylhydrazinyl; here,
Any substitutable member of such group includes alkyl, alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, carbocyclyloxy , Wherein said method is optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl and heterocyclylalkoxy. Y ² is ═C (R ⁴ ) —, and Y ⁴ and Y ⁵ are each ═C (H) —.
The method of claim 1. The method of claim 2, wherein R ⁴ is hydrogen. ^4. The method of claim 3, wherein R ^<3C> is hydrogen. The method of claim 4, wherein R ^3B is hydrogen. The substituted pyrazole has the formula:

And the hydrazone has the following formula:

And the optionally substituted benzoyl halide has the following formula:

The method of claim 5, having the structure: R ^B is chloro The method of claim 6 wherein.   The method of claim 7, wherein the mixture is heated at a temperature greater than 50 ° C for more than 30 minutes.   The method of claim 8, wherein the mixture is heated at a temperature greater than 50 ° C. for at least about 1 hour.   The method of claim 7, wherein the mixture is heated to a temperature greater than 50 ° C and less than or equal to about 65 ° C.   11. The method of claim 10, wherein the mixture is heated to a temperature above 50 ° C. and below about 65 ° C. for more than 30 minutes.   The method of claim 11, wherein the mixture is heated at a temperature greater than 50 ° C. and less than about 65 ° C. for at least about 1 hour. A method for producing a substituted pyrazole, a tautomer of a substituted pyrazole, or a salt of a substituted pyrazole or a tautomer, wherein the substituted pyrazole has the following formula (I):

And the method comprises the following:
More than 30% (wt%) of the composition is of formula (IV):

Producing a composition comprising a protected pyrazole intermediate corresponding in structure to
R ^3A , R ^3B and R ^3C are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy and alkoxyalkyl,
Any carbon of alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy or alkoxyalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and cyano. ;
One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═C (R ⁴ ) —;
One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═N—;
^{Three of} Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are independently selected from the group consisting of ═C (H) — and ═N—;
R ⁴ is hydrogen, halogen, cyano, hydroxy, thiol, carboxy, nitro, alkyl, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxy Carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylthio, carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy, carbocyclylheterocyclyl, heterocyclylalkyl, heterocyclyloxy, Heterocyclylalkoxy, amino, aminoalkyl, alkylamino, alkenylamino, alkini Amino, carbocyclylamino, heterocyclylamino, aminocarbonyl, alkoxy, alkoxyalkyl, alkenyloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, carbocyclyloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxycarboxy Kurylamino, alkoxycarbocyclylalkylamino, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylamino, alkylaminoalkylamino, carbocyclylalkylamino, alkylaminoalkylaminoalkylamino, alkylheterocyclyl Amino, heterocyclylalkylamino, alkylhe Selected from the group consisting of telocyclylalkylamino, carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, alkylaminocarbonyl, alkylcarbonylamino, hydrazinyl, alkylhydrazinyl and carbocyclylhydrazinyl; here,
Any substitutable member of such group is alkyl, alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, carbocyclyloxy , Wherein said method is optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl and heterocyclylalkoxy.   14. The method of claim 13, wherein at least about 50% (wt%) of the composition comprises a protected pyrazole intermediate.   15. The method of claim 14, wherein at least about 75% (wt%) of the composition comprises a protected pyrazole intermediate.   16. The method of claim 15, wherein at least about 95% (wt%) of the composition comprises a protected pyrazole intermediate.   The method of claim 16, wherein at least about 97% (wt%) of the composition comprises a protected pyrazole intermediate.   18. The method of claim 17, wherein at least about 98.5% (wt%) of the composition comprises a protected pyrazole intermediate. Y ² is ═C (R ⁴ ) — and Y ⁴ and Y ⁵ are each ═C (H) —.
The method of claim 13. R ⁴ is hydrogen The process of claim 19 wherein. ^21. The method of claim 20, wherein ^R3C is hydrogen. The method of claim 21, wherein R ^3B is hydrogen. The substituted pyrazole has the following formula:

And the protected pyrazole intermediate has the formula:

23. The method of claim 22 having the structure:   24. The method of claim 23, wherein at least about 50% (wt%) of the composition comprises a protected pyrazole intermediate.   25. The method of claim 24, wherein at least about 75% (wt%) of the composition comprises a protected pyrazole intermediate.   26. The method of claim 25, wherein at least about 95% (wt%) of the composition comprises a protected pyrazole intermediate.   27. The method of claim 26, wherein at least about 97% (wt%) of the composition comprises a protected pyrazole intermediate.   28. The method of claim 27, wherein at least about 98.5% (wt%) of the composition comprises a protected pyrazole intermediate. Production of the composition is as follows:
24. The method of claim 23 comprising contacting water with a mixture comprising a protected pyrazole intermediate, an organic solvent and impurities to form a multiphase mixture, and removing the water containing impurities from the multiphase mixture. Method. Production of the composition is as follows:
Contacting a mixture containing a protected pyrazole intermediate, an organic solvent and impurities with an aqueous salt solution to form a multiphase mixture, and removing water containing the impurities (or salts thereof) from the multiphase mixture. 24. The method of claim 23.   32. The method of claim 30, wherein the aqueous salt solution comprises ammonium and chloride ions.   24. The method of claim 23, wherein producing the composition comprises contacting a mixture comprising a protected pyrazole intermediate and an organic solvent with an antisolvent to produce a solvent / antisolvent mixture. Include the solvent wherein the solvent is selected from the group consisting of tetrahydrofuran and toluene, and the antisolvent is C ₁ -C ₆ - containing alcohol,
The method of claim 32.   34. The method of claim 33, wherein the antisolvent comprises isopropyl alcohol.   33. The method of claim 32, wherein the mixture comprising the protected pyrazole intermediate and the organic solvent is at a temperature greater than 25 ° C when contacted with the mixture comprising the protected pyrazole intermediate and the organic solvent.   35. The method of claim 32, wherein the mixture comprising the protected pyrazole intermediate and the organic solvent is at a temperature of about 50 to about 60C when contacted with the mixture comprising the protected pyrazole intermediate and the organic solvent.   35. The method of claim 32, wherein the antisolvent is at a temperature greater than 25 ° C when contacted with a mixture comprising a protected pyrazole intermediate and an organic solvent.   35. The method of claim 32, wherein the antisolvent is at a temperature of about 50 to about 60 <0> C when contacted with a mixture comprising a protected pyrazole intermediate and an organic solvent.   35. The method of claim 32, wherein generating the composition further comprises heating the solvent / antisolvent mixture.   35. The method of claim 32, wherein the formation of the composition further comprises heating the solvent / antisolvent at a temperature of about 50 to about 60C. More than 30% (wt%) of the composition is of formula (IV):

And said composition comprising compounds corresponding in structure.   42. The composition of claim 41, wherein at least about 50% (wt%) of the composition consists of the compound.   43. The composition of claim 42, wherein at least about 75% (wt%) of the composition consists of the compound.   44. The composition of claim 43, wherein at least about 95% (wt%) of the composition consists of the compound.   45. The composition of claim 44, wherein at least about 97% (wt%) of the composition consists of the compound.   42. The composition of claim 41, wherein at least about 98.5% (wt%) of the composition comprises the compound. Said compound has the following formula:

42. The composition of claim 41, having the structure:   48. The composition of claim 47, wherein at least about 50% (wt%) of the composition consists of the compound.   49. The composition of claim 48, wherein at least about 75% (wt%) of the composition consists of the compound.   50. The composition of claim 49, wherein at least about 95% (wt%) of the composition consists of the compound.   51. The composition of claim 50, wherein at least about 97% (% by weight) of the composition consists of the compound.   52. The composition of claim 51, wherein at least about 98.5% (wt%) of the composition consists of the compound. A method for producing a substituted pyrazole, a tautomer of a substituted pyrazole, or a salt of a substituted pyrazole or a tautomer, wherein the substituted pyrazole has the following formula (I):

And the method comprises reacting the acid and toluene with formula (IV):

In contact with a corresponding protected pyrazole intermediate in structure, wherein
R ^3A , R ^3B and R ^3C are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy and alkoxyalkyl,
Any carbon of alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy or alkoxyalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and cyano. ;
One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═C (R ⁴ ) —;
One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═N—;
^{Three of} Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are independently selected from the group consisting of ═C (H) — and ═N—;
R ⁴ is hydrogen, halogen, cyano, hydroxy, thiol, carboxy, nitro, alkyl, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxy , Carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylthio, carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy, carbocyclylheterocyclyl, heterocyclylalkyl, heterocyclyloxy, Heterocyclylalkoxy, amino, aminoalkyl, alkylamino, alkenylamino, alkini Amino, carbocyclylamino, heterocyclylamino, aminocarbonyl, alkoxy, alkoxyalkyl, alkenyloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, carbocyclyloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxycarboxy Kurylamino, alkoxycarbocyclylalkylamino, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylamino, alkylaminoalkylamino, carbocyclylalkylamino, alkylaminoalkylaminoalkylamino, alkylheterocyclyl Amino, heterocyclylalkylamino, alkylhe Selected from the group consisting of telocyclylalkylamino, carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, alkylaminocarbonyl, alkylcarbonylamino, hydrazinyl, alkylhydrazinyl and carbocyclylhydrazinyl; here,
Any substitutable member of such group includes alkyl, alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, carbocyclyloxy , Wherein said method is optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl and heterocyclylalkoxy. Y ² is ═C (R ⁴ ) —, and Y ⁴ and Y ⁵ are each ═C (H) —.
54. The method of claim 53. R ⁴ is hydrogen The method of claim 54. 56. The method of claim 55, wherein ^R3C is hydrogen. ^57. The method of claim 56, wherein ^R3B is hydrogen. The substituted pyrazole has the following formula:

And the protected pyrazole intermediate has the formula:

58. The method of claim 57, having the structure: A method for producing a substituted pyrazole, a tautomer of a substituted pyrazole, or a salt of a substituted pyrazole or a tautomer, wherein the substituted pyrazole has the following formula (I):

And the method is as follows:
Contacting the protected pyrazole intermediate with an acid to produce an acidic mixture;
Including contacting the acidic mixture with a base and maintaining the temperature of the acidic mixture below 65 ° C. between formation of the acidic mixture and addition of the base, wherein the protected pyrazole intermediate has the formula (IV):

Having the structure of
R ^3A , R ^3B and R ^3C are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy and alkoxyalkyl,
Any carbon of alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy or alkoxyalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and cyano. ;
One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═C (R ⁴ ) —;
One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═N—;
^{Three of} Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are independently selected from the group consisting of ═C (H) — and ═N—;
R ⁴ is hydrogen, halogen, cyano, hydroxy, thiol, carboxy, nitro, alkyl, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxy , Carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylthio, carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy, carbocyclylheterocyclyl, heterocyclylalkyl, heterocyclyloxy, Heterocyclylalkoxy, amino, aminoalkyl, alkylamino, alkenylamino, alkini Amino, carbocyclylamino, heterocyclylamino, aminocarbonyl, alkoxy, alkoxyalkyl, alkenyloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, carbocyclyloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxycarboxy Kurylamino, alkoxycarbocyclylalkylamino, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylamino, alkylaminoalkylamino, carbocyclylalkylamino, alkylaminoalkylaminoalkylamino, alkylheterocyclyl Amino, heterocyclylalkylamino, alkylhe Selected from the group consisting of telocyclylalkylamino, carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, alkylaminocarbonyl, alkylcarbonylamino, hydrazinyl, alkylhydrazinyl and carbocyclylhydrazinyl; here,
Any substitutable member of such group includes alkyl, alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, carbocyclyloxy , Wherein said method is optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl and heterocyclylalkoxy. Y ² is ═C (R ⁴ ) —, and Y ⁴ and Y ⁵ are each ═C (H) —.
60. The method of claim 59. R ⁴ is hydrogen, 61. The method of claim 60, wherein. 62. The method of claim 61, wherein ^R3C is hydrogen. 64. The method of claim 62, wherein ^R3B is hydrogen. The substituted pyrazole has the following formula:

And the protected pyrazole intermediate has the formula:

64. The method of claim 63, having the structure: A method for producing a substituted pyrazole, a tautomer of a substituted pyrazole, or a salt of a substituted pyrazole or a tautomer, wherein the substituted pyrazole has the formula (I):

And the method comprises the following:
Contacting the protected pyrazole intermediate with an acid to produce an acidic mixture;
Contacting the acidic mixture with a base to produce a mixture having a higher pH, and heating the mixture having a higher pH to a temperature above 25 ° C., wherein the protected pyrazole intermediate is: Formula (IV):

Having the structure of
R ^3A , R ^3B and R ^3C are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy and alkoxyalkyl,
Any carbon of alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy or alkoxyalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and cyano. ;
One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═C (R ⁴ ) —;
One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═N—;
^{Three of} Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are independently selected from the group consisting of ═C (H) — and ═N—;
R ⁴ is hydrogen, halogen, cyano, hydroxy, thiol, carboxy, nitro, alkyl, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxy , Carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylthio, carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy, carbocyclylheterocyclyl, heterocyclylalkyl, heterocyclyloxy, Heterocyclylalkoxy, amino, aminoalkyl, alkylamino, alkenylamino, alkini Amino, carbocyclylamino, heterocyclylamino, aminocarbonyl, alkoxy, alkoxyalkyl, alkenyloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, carbocyclyloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxycarboxy Kurylamino, alkoxycarbocyclylalkylamino, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylamino, alkylaminoalkylamino, carbocyclylalkylamino, alkylaminoalkylaminoalkylamino, alkylheterocyclyl Amino, heterocyclylalkylamino, alkylhe Selected from the group consisting of telocyclylalkylamino, carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, alkylaminocarbonyl, alkylcarbonylamino, hydrazinyl, alkylhydrazinyl and carbocyclylhydrazinyl; here,
Any substitutable member of such group includes alkyl, alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, carbocyclyloxy , Wherein said method is optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl and heterocyclylalkoxy.   66. The method of claim 65, wherein the temperature of the higher pH mixture is greater than 25 [deg.] C and held for at least about 1 hour.   66. The method of claim 65, wherein the higher pH mixture is heated to a temperature of about 65 to about 80C.   66. The method of claim 65, wherein the higher pH mixture is heated at about 65 to about 80 C for at least about 1 hour. Y ² is ═C (R ⁴ ) —, and Y ⁴ and Y ⁵ are each ═C (H) —.
66. The method of claim 65. R ⁴ is hydrogen The method of claim 69. ^72. The method of claim 70, wherein ^R3C is hydrogen. ^72. The method of claim 71, wherein ^R3B is hydrogen. The substituted pyrazole has the following formula:

And the protected pyrazole intermediate has the formula:

73. The method of claim 72, having the structure:   74. The method of claim 73, wherein the temperature of the higher pH mixture is greater than 25 ° C and held for at least about 1 hour.   74. The method of claim 73, wherein the higher pH mixture is heated to a temperature of about 65 to about 80C.   74. The method of claim 73, wherein the higher pH mixture is heated at about 65 to about 80 <0> C for at least about 1 hour. A method for producing a substituted pyrazole, a tautomer of a substituted pyrazole, or a salt of a substituted pyrazole or a tautomer, wherein the substituted pyrazole has the formula (I):

And contacting an unsubstituted piperidinyl intermediate with acetonitrile to produce a mixture comprising acetonitrile and the unsubstituted piperidinyl intermediate, comprising:
The unsubstituted piperidinyl intermediate is represented by formula (V):

Having the structure of
R ^3A , R ^3B and R ^3C are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy and alkoxyalkyl,
Any carbon of alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy or alkoxyalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and cyano. ;
One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═C (R ⁴ ) —;
One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═N—;
^{Three of} Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are independently selected from the group consisting of ═C (H) — and ═N—;
R ⁴ is hydrogen, halogen, cyano, hydroxy, thiol, carboxy, nitro, alkyl, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxy Carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylthio, carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy, carbocyclylheterocyclyl, heterocyclylalkyl, heterocyclyloxy, Heterocyclylalkoxy, amino, aminoalkyl, alkylamino, alkenylamino, alkini Amino, carbocyclylamino, heterocyclylamino, aminocarbonyl, alkoxy, alkoxyalkyl, alkenyloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, carbocyclyloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxycarboxy Kurylamino, alkoxycarbocyclylalkylamino, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylamino, alkylaminoalkylamino, carbocyclylalkylamino, alkylaminoalkylaminoalkylamino, alkylheterocyclyl Amino, heterocyclylalkylamino, alkylhe Selected from the group consisting of telocyclylalkylamino, carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, alkylaminocarbonyl, alkylcarbonylamino, hydrazinyl, alkylhydrazinyl and carbocyclylhydrazinyl; here,
Any substitutable member of such group is alkyl, alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, carbocyclyloxy , Wherein said method is optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl and heterocyclylalkoxy.   78. The method of claim 77, wherein the ratio of acetonitrile to unsubstituted piperidinyl intermediate in the mixture is at least about 4: 1 (acetonitrile (ml): unsubstituted piperidinyl intermediate (grams)).   78. The method of claim 77, wherein the mixture is heated to a temperature greater than 25 ° C.   80. The method of claim 79, wherein the temperature of the mixture is greater than 25 ° C for at least about 1 hour.   80. The method of claim 79, wherein the mixture is heated to a temperature of at least about 75 ° C.   82. The method of claim 81, wherein the mixture is heated such that the temperature of the mixture is at least about 75 ° C for at least about 1 hour.   82. The method of claim 81, wherein the heated mixture is cooled to a temperature of about 2C to about 20C.   80. The method of claim 79, wherein the heated mixture is cooled to a temperature of about 2C to about 20C. Y ² is ═C (R ⁴ ) —, and Y ⁴ and Y ⁵ are each ═C (H) —.
78. The method of claim 77. R ⁴ is hydrogen, 85. The method according. ^90. The method of claim 86, wherein ^R3C is hydrogen. ^90. The method of claim 87, wherein ^R3B is hydrogen. The substituted pyrazole has the following formula:

And the unsubstituted piperidinyl intermediate has the formula:

90. The method of claim 88, having the structure:   90. The method of claim 89, wherein the ratio of acetonitrile to unsubstituted piperidinyl intermediate in the mixture is at least about 4: 1 (acetonitrile (ml): unsubstituted piperidinyl intermediate (grams)).   90. The method of claim 89, wherein the mixture is heated to a temperature greater than 25 ° C.   92. The method of claim 91, wherein the temperature of the mixture is greater than 25 [deg.] C for at least about 1 hour.   92. The method of claim 91, wherein the mixture is heated to a temperature of at least about 75 ° C.   94. The method of claim 93, wherein the mixture is heated such that the temperature of the mixture is at least about 75 [deg.] C for at least about 1 hour.   94. The method of claim 93, wherein the heated mixture is cooled to a temperature of about 2 <0> C to less than about 20 <0> C.   92. The method of claim 91, wherein the heated mixture is cooled to a temperature of about 2 <0> C to less than about 20 <0> C. A method for producing a substituted pyrazole, a tautomer of a substituted pyrazole, or a salt of a substituted pyrazole or a tautomer, wherein the substituted pyrazole has the formula (I):

And the process comprises the glycolate ester of formula (V):

Comprising reacting with a corresponding unsubstituted piperidinyl intermediate in structure, wherein
R ^3A , R ^3B and R ^3C are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy and alkoxyalkyl,
Any carbon of alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy or alkoxyalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and cyano. ;
One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═C (R ⁴ ) —;
One of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is ═N—;
^{Three of} Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are independently selected from the group consisting of ═C (H) — and ═N—;
R ⁴ is hydrogen, halogen, cyano, hydroxy, thiol, carboxy, nitro, alkyl, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxy Carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylthio, carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy, carbocyclylheterocyclyl, heterocyclylalkyl, heterocyclyloxy, Heterocyclylalkoxy, amino, aminoalkyl, alkylamino, alkenylamino, alkini Amino, carbocyclylamino, heterocyclylamino, aminocarbonyl, alkoxy, alkoxyalkyl, alkenyloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, carbocyclyloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxycarboxy Kurylamino, alkoxycarbocyclylalkylamino, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylamino, alkylaminoalkylamino, carbocyclylalkylamino, alkylaminoalkylaminoalkylamino, alkylheterocyclyl Amino, heterocyclylalkylamino, alkylhe Selected from the group consisting of telocyclylalkylamino, carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, alkylaminocarbonyl, alkylcarbonylamino, hydrazinyl, alkylhydrazinyl and carbocyclylhydrazinyl; here,
Any substitutable member of such group is alkyl, alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, carbocyclyloxy , Wherein said method is optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl and heterocyclylalkoxy. Y ² is ═C (R ⁴ ) —, and Y ⁴ and Y ⁵ are each ═C (H) —.
98. The method of claim 97. R ⁴ is hydrogen, claim 98 A method according. ^100. The method of claim 99, wherein ^R3C is hydrogen. ^101. The method of claim 100, wherein ^R3B is hydrogen. The substituted pyrazole has the following formula:

And the unsubstituted piperidinyl intermediate has the formula:

102. The method of claim 101, having the structure: The glycolic acid ester C ₁ -C ₆ - alkyl glycolate, claim 102 method described.   104. The method of claim 103, wherein the glycolic acid ester is ethyl glycolate.   104. The method of claim 103, wherein the glycolic acid ester is butyl glycolate.   103. The method of claim 102, wherein the glycolic acid ester is reacted with an unsubstituted piperidinyl intermediate in the presence of 1,5-diazabicyclo [4.3.0] non-5-ene.   105. The method of claim 102, wherein the glycolic acid ester is reacted with an unsubstituted piperidinyl intermediate in the presence of 1,8-diazabicyclo [5.4.0] undec-7-ene.   103. The method of claim 102, wherein the glycolic acid ester is reacted with 5- (4-piperidyl) -4- (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole in the presence of a polar aprotic solvent.   109. The method of claim 108, wherein the polar aprotic solvent is selected from the group consisting of dimethyl sulfoxide and dimethylformamide.   109. The method of claim 108, wherein the polar aprotic solvent is N-methylpyrrolidinone.   The glycolic acid ester is 5- (4-piperidyl) -4- (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole in the presence of 1,8-diazabicyclo [5.4.0] undec-7-ene. 111. The method of claim 110, wherein the method is reacted with.   112. The method of claim 111, wherein the glycolic acid ester is butyl glycolate.   113. The method of claim 112, wherein the butyl glycolate is reacted with 5- (4-piperidyl) -4- (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole in the presence of heat.   The glycolic ester is reacted with 5- (4-piperidyl) -4- (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole at a temperature higher than 25 ° C. to give N- (2-hydroxyacetyl)- 105. The method of claim 102, wherein the method produces a product mixture comprising 5- (4-piperidyl) -4- (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole.   119. The method of claim 114, further comprising cooling the product mixture to a temperature below 20 ° C after heating.   116. The method of claim 115, wherein the antisolvent is present in the product mixture during at least a portion of the cooling of the product mixture.   117. The method of claim 116, wherein the antisolvent comprises ethanol.   105. The method further comprises producing a solvate of N- (2-hydroxyacetyl) -5- (4-piperidyl) -4- (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole. the method of.   119. The method of claim 118 further comprising producing Form I crystalline N- (2-hydroxyacetyl) -5- (4-piperidyl) -4- (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole. Method.   The solvate is an N-methylpyrrolidinone solvate of N- (2-hydroxyacetyl) -5- (4-piperidyl) -4- (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole. 119. The method according to item 118.   121. The method of claim 120, further comprising producing Form I crystalline N- (2-hydroxyacetyl) -5- (4-piperidyl) -4- (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole. Method.   121. The method of claim 120, wherein the N-methylpyrrolidinone solvate is produced in the presence of an antisolvent.   123. The method of claim 122, wherein the antisolvent comprises ethanol. below:
123. The method of claim 120, further comprising forming the mixture by a process comprising introducing N-methylpyrrolidinone solvate and polar solvent (not N-methylpyrrolidinone) into the reactor and heating the mixture. Method.   125. The method of claim 124, wherein the polar solvent in the mixture comprises water.   125. The method of claim 124, wherein the polar solvent in the mixture comprises isopropyl alcohol.   125. The method of claim 124, wherein the polar solvent in the mixture comprises ethanol.   129. The method of claim 124, wherein the mixture is heated to a temperature greater than 25 ° C.   129. The method of claim 124, wherein the mixture is heated to a temperature of at least about 50 ° C.   129. The method of claim 128, wherein the mixture is refluxed.   129. The method of claim 128, wherein the mixture is heated at a temperature of at least about 50 ° C for longer than about 1 hour.   132. The method of claim 131, wherein the mixture is refluxed for more than 1 hour.   132. The method of claim 131, wherein the polar solvent in the mixture comprises ethanol.   129. The method of claim 124, further comprising cooling the mixture to a temperature below 20 ° C after heating. below:
Producing a mixture by a process comprising introducing hydrazone and optionally substituted benzoyl halide into the reactor, and heating the mixture to a temperature greater than 50 ° C .;
98. The method of claim 97, further comprising: wherein the hydrazone has the following formula (II):

And the optionally substituted benzoyl halide has the following formula (III):

(Wherein, R ^B is halogen) said method comprising the structure. More than 30% (wt%) of the composition has the following formula (IV):

98. The method of claim 97, further comprising producing a composition comprising a protected pyrazole intermediate having the structure: The acid and toluene are converted to the following formula (IV):

98. The method of claim 97, further comprising contacting with a protected pyrazole intermediate having the structure: below:
Contacting the protected pyrazole intermediate with an acid to produce an acidic mixture;
98. The method of claim 97, further comprising contacting the acidic mixture with a base and maintaining the temperature of the acidic mixture below 65 ° C. between the formation of the acidic mixture and the addition of the base. Pyrazole intermediates have the following formula (IV):

The method having the structure: below:
Contacting the protected pyrazole intermediate with an acid to produce an acidic mixture;
Contacting the acidic mixture with a base to produce a mixture having a higher pH, and heating the mixture having a higher pH to a temperature greater than 25 ° C.,
99. The method of claim 97, wherein the protected pyrazole intermediate is of the following formula (IV):

The method having the structure:   98. The method of claim 97, further comprising contacting the unsubstituted piperidinyl intermediate with acetonitrile prior to reacting the unsubstituted piperidinyl intermediate with glycolate. below:
Producing a mixture by a process comprising introducing hydrazone and optionally substituted benzoyl halide into the reactor, and heating the mixture to a temperature above 50 ° C .;
Producing a composition in which more than 30% (wt%) of the composition consists of a protected pyrazole intermediate;
below:
Contacting the acid and toluene with a composition comprising the protected pyrazole intermediate to produce an acidic mixture;
Contacting the acidic mixture with a base to produce a mixture having a higher pH, and producing an unsubstituted piperidinyl intermediate by a process comprising heating the mixture having a higher pH to a temperature greater than 25 ° C .;
98. The method of claim 97, comprising contacting an unsubstituted piperidinyl intermediate with acetonitrile and then reacting the unsubstituted piperidinyl intermediate with a glycolate, wherein the hydrazone has the following formula (II):

And the optionally substituted benzoyl halide has the following formula (III):

And the protected pyrazole intermediate has the following formula (IV):

(Wherein, R ^B is a halogen) having a structure of the method. below:
Producing a mixture by a process comprising introducing hydrazone and optionally substituted benzoyl halide into the reactor, and heating the mixture to a temperature above 50 ° C. and below 65 ° C .;
Producing a composition in which more than 90% (wt%) of the composition consists of a protected pyrazole intermediate;
below:
HCl and toluene are contacted with a composition comprising a protected pyrazole intermediate to produce an acidic mixture;
The acidic mixture is contacted with NaOH to produce a mixture having a higher pH and an unsubstituted piperidinyl intermediate is produced by a process comprising heating the mixture having a higher pH to a temperature of about 65 to about 80 ° C. And
Including contacting the unsubstituted piperidinyl intermediate with acetonitrile and then reacting the unsubstituted piperidinyl intermediate with butyl glycolate in the presence of 1,8-diazabicyclo [5.4.0] undec-7-ene. 99. The method of claim 97, wherein the substituted pyrazole has the formula:

And the hydrazone has the following formula:

And the optionally substituted benzoyl halide has the following formula:

And the protected pyrazole intermediate has the formula:

And the unsubstituted piperidinyl intermediate has the formula:

The method having the structure:   143. The method of claim 142, wherein the temperature of the acidic mixture is maintained below about 30 ° C during the formation of the acidic mixture and addition of NaOH.   9. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of the substituted pyrazole or tautomer according to claim 1.   7. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of a substituted pyrazole or tautomer as claimed in claim 6.   A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of a substituted pyrazole or tautomer as claimed in claim 13.   24. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of a substituted pyrazole or tautomer as claimed in claim 23.   54. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of a substituted pyrazole or tautomer as claimed in claim 53.   59. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of the substituted pyrazole or tautomer according to claim 58.   60. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of the substituted pyrazole or tautomer according to claim 59.   65. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of a substituted pyrazole or tautomer as claimed in claim 64.   68. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of a substituted pyrazole or tautomer as claimed in claim 65.   74. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of a substituted pyrazole or tautomer as claimed in claim 73.   78. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of a substituted pyrazole or tautomer according to claim 77.   90. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of a substituted pyrazole or tautomer according to claim 89.   98. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of a substituted pyrazole or tautomer as claimed in claim 97.   103. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of a substituted pyrazole or tautomer as described in claim 102.   143. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrazole, a tautomer of a substituted pyrazole, or a pharmaceutically acceptable salt of a substituted pyrazole or tautomer according to claim 142.